PIBs as modifiers of the p53 pathway and methods of use

ABSTRACT

Human PIB genes are identified as modulators of the p53 pathway, and thus are therapeutic targets for disorders associated with defective p53 function. Methods for identifying modulators of p53, comprising screening for agents that modulate the activity of PIB are provided.

REFERENCE TO RELATED APPLICATIONS

[0001] This application claims priority to U.S. provisional patentapplications No. 60/296,076 filed Jun. 5, 2001, No. 60/328,605 filedOct. 10, 2001, and No. 60/357,253 filed Feb. 15, 2002. The contents ofthe prior applications are hereby incorporated in their entirety.

BACKGROUND OF THE INVENTION

[0002] The p53 gene is mutated in over 50 different types of humancancers, including familial and spontaneous cancers, and is believed tobe the most commonly mutated gene in human cancer (Zambetti and Levine,FASEB (1993) 7:855-865; Hollstein, et al., Nucleic Acids Res. (1994)22:3551-3555). Greater than 90% of mutations in the p53 gene aremissense mutations that alter a single amino acid that inactivates p53function. Aberrant forms of human p53 are associated with poorprognosis, more aggressive tumors, metastasis, and short survival rates(Mitsudomi et al., Clin Cancer Res 2000 Oct; 6(10):4055-63; Koshland,Science (1993) 262:1953).

[0003] The human p53 protein normally functions as a central integratorof signals including DNA damage, hypoxia, nucleotide deprivation, andoncogene activation (Prives, Cell (1998) 95:5-8). In response to thesesignals, p53 protein levels are greatly increased with the result thatthe accumulated p53 activates cell cycle arrest or apoptosis dependingon the nature and strength of these signals. Indeed, multiple lines ofexperimental evidence have pointed to a key role for p53 as a tumorsuppressor (Levine, Cell (1997) 88:323-331). For example, homozygous p53“knockout” mice are developmentally normal but exhibit nearly 100%incidence of neoplasia in the first year of life (Donehower et al.,Nature (1992) 356:215-221).

[0004] The biochemical mechanisms and pathways through which p53functions in normal and cancerous cells are not fully understood, butone clearly important aspect of p53 function is its activity as agene-specific transcriptional activator. Among the genes with knownp53-response elements are several with well-characterized roles ineither regulation of the cell cycle or apoptosis, including GADD45,p21/Waf1/Cip1, cyclin G, Bax, IGF-BP3, and MDM2 (Levine, Cell (1997)88:323-331).

[0005] The inositol polyphosphate 5-phosphatases are a family of enzymesthat terminate the signals generated by the phosphoinositide kinases andphospholipase C. Given the diverse signaling functions of both thepolyphosphoinositides and Ins P3, it is predicted that the5-phosphatases play a critical role in the regulation of many cellularevents, in particular membrane trafficking and cell growth (Mitchell, C.et al. (1996) Biochem Soc Trans. 24:994-1000).

[0006] Phosphatidylinositol bisphosphate 5-phosphatase A (PIB5PA) mayplay a role in polyphosphate catabolism (Mochizuki, Y. and Takenawa, T.(1999) J. Biol. Chem. 274: 36790-36795). PIB5PA is expressed in brain,heart, kidney, stomach, small intestine, and lung as well as a varietyof human, rat, and mouse cell lines. PIB5PA is classified as a type II5-phosphatase because of its hydrolyzed phosphate at the D-5 position ofPtdIns P2, Ins P3, and Ins P4 (Mochizuki, Y. and Takenawa, T. (1999)supra). PIB5PA localizes in the cytoplasm and at ruffling membranes. Itis believed that PIB5PA does not participate in the reorganization ofthe actin cytoskeleton but may be involved in modulation of the functionof inositol and phosphatidylinositol polyphosphate-binding proteins thatare present at membrane ruffles. PIB5PA is expressed in humanlymphoblastic leukemia and myeloid leukemia cells (Mochizuki, Y. andTakenawa, T. (1999)supra).

[0007] Skeletal muscle and kidney-enriched inositol phosphatase (SKIP)is an inositol polyphosphate 5-phosphatase that may negatively regulatethe actin cytoskeleton by hydrolyzing PtdIns 4,5-bisphosphate. Itcontains two highly conserved catalytic motifs for 5-phosphatase and isubiquitously expressed with highest expression levels found in skeletalmuscle, heart, and kidney. SKIP is a simple 5-phosphatase with no othermotifs. Expression studies indicate that SKIP 5-phosphatase showactivities toward inositol 1,4,5-trisphosphate, inositol1,3,4,5-tetrakisphosphate, phosphatidylinositol (PtdIns)4,5-bisphosphate, and PtdIns 3,4, 5-trisphosphate but has 6-fold moresubstrate specificity for PtdIns 4,5-bisphosphate than for inositol 1,4,5-trisphosphate (Ijuin T, et al. (2000) J Biol Chem 275:10870-10875).SKIP is expressed in cytosol and the loss of actin stress fibers occurswhere the SKIP protein is concentrated.

[0008] The ability to manipulate the genomes of model organisms such asDrosophila provides a powerful means to analyze biochemical processesthat, due to significant evolutionary conservation, has direct relevanceto more complex vertebrate organisms. Due to a high level of gene andpathway conservation, the strong similarity of cellular processes, andthe functional conservation of genes between these model organisms andmammals, identification of the involvement of novel genes in particularpathways and their functions in such model organisms can directlycontribute to the understanding of the correlative pathways and methodsof modulating them in mammals (see, for example, Mechler B M et al.,1985 EMBO J 4:1551-1557; Gateff E. 1982 Adv. Cancer Res. 37: 33-74;Watson K L., et al., 1994 J Cell Sci. 18: 19-33; Miklos G L, and Rubin GM. 1996 Cell 86:521-529; Wassarman D A, et al., 1995 Curr Opin Gen Dev5: 44-50; and Booth D R. 1999 Cancer Metastasis Rev. 18: 261-284). Forexample, a genetic screen can be carried out in an invertebrate modelorganism having underexpression (e.g. knockout) or overexpression of agene (referred to as a “genetic entry point”) that yields a visiblephenotype. Additional genes are mutated in a random or targeted manner.When a gene mutation changes the original phenotype caused by themutation in the genetic entry point, the gene is identified as a“modifier” involved in the same or overlapping pathway as the geneticentry point. When the genetic entry point is an ortholog of a human geneimplicated in a disease pathway, such as p53, modifier genes can beidentified that may be attractive candidate targets for noveltherapeutics.

[0009] All references cited herein, including sequence information inreferenced Genbank identifier numbers and website references, areincorporated herein in their entireties.

SUMMARY OF THE INVENTION

[0010] We have discovered genes that modify the p53 pathway inDrosophila, and identified their human orthologs, hereinafter referredto as phosphatidylinositol biphosphate (PIB). The invention providesmethods for utilizing these p53 modifier genes and polypeptides toidentify candidate therapeutic agents that can be used in the treatmentof disorders associated with defective p53 function. PreferredPIB-modulating agents specifically bind to PIB polypeptides and restorep53 function. Other preferred PIB-modulating agents are nucleic acidmodulators such as antisense oligomers and RNAi that repress PIB geneexpression or product activity by, for example, binding to andinhibiting the respective nucleic acid (i.e. DNA or mRNA).

[0011] PIB-specific modulating agents may be evaluated by any convenientin vitro or in vivo assay for molecular interaction with a PIBpolypeptide or nucleic acid. In one embodiment, candidate p53 modulatingagents are tested with an assay system comprising a PIB polypeptide ornucleic acid. Candidate agents that produce a change in the activity ofthe assay system relative to controls are identified as candidate p53modulating agents. The assay system may be cell-based or cell-free.PIB-modulating agents include PIB related proteins (e.g. dominantnegative mutants, and biotherapeutics); PIB-specific antibodies;PIB-specific antisense oligomers and other nucleic acid modulators; andchemical agents that specifically bind PIB or compete with PIB bindingtarget. In one specific embodiment, a small molecule modulator isidentified using a phosphatase assay. In specific embodiments, thescreening assay system is selected from a binding assay, an apoptosisassay, a cell proliferation assay, an angiogenesis assay, and a hypoxicinduction assay.

[0012] In another embodiment, candidate p53 pathway modulating agentsare further tested using a second assay system that detects changes inthe p53 pathway, such as angiogenic, apoptotic, or cell proliferationchanges produced by the originally identified candidate agent or anagent derived from the original agent. The second assay system may usecultured cells or non-human animals. In specific embodiments, thesecondary assay system uses non-human animals, including animalspredetermined to have a disease or disorder implicating the p53 pathway,such as an angiogenic, apoptotic, or cell proliferation disorder (e.g.cancer).

[0013] The invention further provides methods for modulating the p53pathway in a mammalian cell by contacting the mammalian cell with anagent that specifically binds a PIB polypeptide or nucleic acid. Theagent may be a small molecule modulator, a nucleic acid modulator, or anantibody and may be administered to a mammalian animal predetermined tohave a pathology associated the p53 pathway.

DETAILED DESCRIPTION OF THE INVENTION

[0014] Genetic screens were designed to identify modifiers of the p53pathway in Drosophila in which p53 was overexpressed in the wing(Ollmann M, et al., Cell 2000 101: 91-101). The CG6805 gene wasidentified as a modifier of the p53 pathway. Accordingly, vertebrateorthologs of these modifiers, and preferably the human orthologs,phosphatidylinositol biphosphate (PIB) genes (i.e., nucleic acids andpolypeptides) are attractive drug targets for the treatment ofpathologies associated with a defective p53 signaling pathway, such ascancer.

[0015] In vitro and in vivo methods of assessing PIB function areprovided herein. Modulation of the PIB or their respective bindingpartners is useful for understanding the association of the p53 pathwayand its members in normal and disease conditions and for developingdiagnostics and therapeutic modalities for p53 related pathologies.PIB-modulating agents that act by inhibiting or enhancing PIBexpression, directly or indirectly, for example, by affecting a PIBfunction such as enzymatic (e.g., catalytic) or binding activity, can beidentified using methods provided herein. PIB modulating agents areuseful in diagnosis, therapy and pharmaceutical development.

[0016] Nucleic Acids and Polypeptides of the Invention

[0017] Sequences related to PIB nucleic acids and polypeptides that canbe used in the invention are disclosed in Genbank (referenced by Genbankidentifier (GI) number) as GI#s 4156153 (SEQ ID NO:1), 18593949 (SEQ IDNO:2), 13652963 (SEQ ID NO:4), 7209854 (SEQ ID NO:5), and 7209856 (SEQID NO:6) for nucleic acid, and GI#s 4314432 (SEQ ID NO:10), 11426729(SEQ ID NO:11), 7706565 (SEQ ID NO:12), 7209857 (SEQ ID NO:13), and13279338 (SEQ ID NO:14) for polypeptides. Additionally, nucleic acids ofSEQ ID NOs:3, 7, 8, and 9 can also be used in the invention.

[0018] PIBs are phosphatase proteins with catalytic domains. The term“PIB polypeptide” refers to a full-length PIB protein or a functionallyactive fragment or derivative thereof. A “functionally active” PIBfragment or derivative exhibits one or more functional activitiesassociated with a full-length, wild-type PIB protein, such as antigenicor immunogenic activity, enzymatic activity, ability to bind naturalcellular substrates, etc. The functional activity of PIB proteins,derivatives and fragments can be assayed by various methods known to oneskilled in the art (Current Protocols in Protein Science (1998) Coliganet al., eds., John Wiley & Sons, Inc., Somerset, N.J.) and as furtherdiscussed below. For purposes herein, functionally active fragments alsoinclude those fragments that comprise one or more structural domains ofa PIB, such as a catalytic domain or a binding domain. Protein domainscan be identified using the PFAM program (Bateman A., et al., NucleicAcids Res, 1999, 27:260-2; http://pfam.wustl.edu). For example, theInositol polyphosphate phosphatase family, catalytic (IPPC) domain ofPIB from GI# 4314432 (SEQ ID NO:10) is located at approximately aminoacid residues 433-512 and 545-786 (PFAM00783). Likewise, the IPPC domainof PIB from GI# 13279338 (SEQ ID NO:14) is located at approximatelyamino acid residues 12-326. Methods for obtaining PIB polypeptides arealso further described below. In some embodiments, preferred fragmentsare functionally active, domain-containing fragments comprising at least25 contiguous amino acids, preferably at least 50, more preferably 75,and most preferably at least 100 contiguous amino acids of any one ofSEQ ID NOs:10, 11, 12, 13, or 14 (a PIB). In further preferredembodiments, the fragment comprises the entire catalytic (functionallyactive) domain.

[0019] The term “PIB nucleic acid” refers to a DNA or RNA molecule thatencodes a PIB polypeptide. Preferably, the PIB polypeptide or nucleicacid or fragment thereof is from a human, but can also be an ortholog,or derivative thereof with at least 70% sequence identity, preferably atleast 80%, more preferably 85%, still more preferably 90%, and mostpreferably at least 95% sequence identity with PIB. Normally, orthologsin different species retain the same function, due to presence of one ormore protein motifs and/or 3-dimensional structures. Orthologs aregenerally identified by sequence homology analysis, such as BLASTanalysis, usually using protein bait sequences. Sequences are assignedas a potential ortholog if the best hit sequence from the forward BLASTresult retrieves the original query sequence in the reverse BLAST(Huynen MA and Bork P, Proc Natl Acad Sci (1998) 95:5849-5856; Huynen MAet al., Genome Research (2000) 10:1204-1210). Programs for multiplesequence alignment, such as CLUSTAL (Thompson JD et al, 1994, NucleicAcids Res 22:4673-4680) may be used to highlight conserved regionsand/or residues of orthologous proteins and to generate phylogenetictrees. In a phylogenetic tree representing multiple homologous sequencesfrom diverse species (e.g., retrieved through BLAST analysis),orthologous sequences from two species generally appear closest on thetree with respect to all other sequences from these two species.Structural threading or other analysis of protein folding (e.g., usingsoftware by ProCeryon, Biosciences, Salzburg, Austria) may also identifypotential orthologs. In evolution, when a gene duplication event followsspeciation, a single gene in one species, such as Drosophila, maycorrespond to multiple genes (paralogs) in another, such as human. Asused herein, the term “orthologs” encompasses paralogs. As used herein,“percent (%) sequence identity” with respect to a subject sequence, or aspecified portion of a subject sequence, is defined as the percentage ofnucleotides or amino acids in the candidate derivative sequenceidentical with the nucleotides or amino acids in the subject sequence(or specified portion thereof), after aligning the sequences andintroducing gaps, if necessary to achieve the maximum percent sequenceidentity, as generated by the program WU-BLAST-2.0a19 (Altschul et al.,J. Mol. Biol. (1997) 215:403-410;http://blast.wustl.edu/blast/README.html) with all the search parametersset to default values. The HSP S and HSP S2 parameters are dynamicvalues and are established by the program itself depending upon thecomposition of the particular sequence and composition of the particulardatabase against which the sequence of interest is being searched. A %identity value is determined by the number of matching identicalnucleotides or amino acids divided by the sequence length for which thepercent identity is being reported. “Percent (%) amino acid sequencesimilarity” is determined by doing the same calculation as fordetermining % amino acid sequence identity, but including conservativeamino acid substitutions in addition to identical amino acids in thecomputation.

[0020] A conservative amino acid substitution is one in which an aminoacid is substituted for another amino acid having similar propertiessuch that the folding or activity of the protein is not significantlyaffected. Aromatic amino acids that can be substituted for each otherare phenylalanine, tryptophan, and tyrosine; interchangeable hydrophobicamino acids are leucine, isoleucine, methionine, and valine;interchangeable polar amino acids are glutamine and asparagine;interchangeable basic amino acids are arginine, lysine and histidine;interchangeable acidic amino acids are aspartic acid and glutamic acid;and interchangeable small amino acids are alanine, serine, threonine,cysteine and glycine.

[0021] Alternatively, an alignment for nucleic acid sequences isprovided by the local homology algorithm of Smith and Waterman (Smithand Waterman, 1981, Advances in Applied Mathematics 2:482-489; database:European Bioinformatics Institute http://www.ebi.ac.uk/MPsrch/; Smithand Waterman, 1981, J. of Molec.Biol., 147:195-197; Nicholas et al.,1998, “A Tutorial on Searching Sequence Databases and Sequence ScoringMethods” (www.psc.edu) and references cited therein.; W. R. Pearson,1991, Genomics 11:635-650). This algorithm can be applied to amino acidsequences by using the scoring matrix developed by Dayhoff (Dayhoff:Atlas of Protein Sequences and Structure, M. O. Dayhoff ed., 5 suppl.3:353-358, National Biomedical Research Foundation, Washington, D.C.,USA), and normalized by Gribskov (Gribskov 1986 Nucl. Acids Res.14(6):6745-6763). The Smith-Waterman algorithm may be employed wheredefault parameters are used for scoring (for example, gap open penaltyof 12, gap extension penalty of two). From the data generated, the“Match” value reflects “sequence identity.”

[0022] Derivative nucleic acid molecules of the subject nucleic acidmolecules include sequences that hybridize to the nucleic acid sequenceof any of SEQ ID NOs:1, 2, 3, 4, 5, 6, 7, 8, or 9. The stringency ofhybridization can be controlled by temperature, ionic strength, pH, andthe presence of denaturing agents such as formamide during hybridizationand washing. Conditions routinely used are set out in readily availableprocedure texts (e.g., Current Protocol in Molecular Biology, Vol. 1,Chap. 2.10, John Wiley & Sons, Publishers (1994); Sambrook et al.,Molecular Cloning, Cold Spring Harbor (1989)). In some embodiments, anucleic acid molecule of the invention is capable of hybridizing to anucleic acid molecule containing the nucleotide sequence of anyone ofSEQ ID NOs:1, 2, ,3 ,4 ,5 , 6,7 8, or 9 under stringent hybridizationconditions that comprise: prehybridization of filters containing nucleicacid for 8 hours to overnight at 65° C. in a solution comprising 6×single strength citrate (SSC) (1× SSC is 0.15 M NaCl, 0.015 M Nacitrate; pH 7.0), 5× Denhardt's solution, 0.05% sodium pyrophosphate and100 μg/ml herring sperm DNA; hybridization for 18-20 hours at 65° C. ina solution containing 6× SSC, 1× Denhardt's solution, 100 μg/ml yeasttRNA and 0.05% sodium pyrophosphate; and washing of filters at 65° C.for 1 h in a solution containing 0.2× SSC and 0.1% SDS (sodium dodecylsulfate).

[0023] In other embodiments, moderately stringent hybridizationconditions are used that comprise: pretreatment of filters containingnucleic acid for 6 h at 40° C. in a solution containing 35% formamide,5× SSC, 50 mM Tris-HCl (pH 7.5), 5 mM EDTA, 0.1% PVP, 0.1% Ficoll, 1%BSA, and 500 μg/ml denatured salmon sperm DNA; hybridization for 18-20hat 40° C. in a solution containing 35% formamide, 5× SSC, 50 mM Tris-HCl(pH 7.5), 5 mM EDTA, 0.02% PVP, 0.02% Ficoll, 0.2% BSA, 100 μg/ml salmonsperm DNA, and 10% (wt/vol) dextran sulfate; followed by washing twicefor 1 hour at 55° C. in a solution containing 2× SSC and 0.1% SDS.

[0024] Alternatively, low stringency conditions can be used thatcomprise: incubation for 8 hours to overnight at 37° C. in a solutioncomprising 20% formamide, 5× SSC, 50 mM sodium phosphate (pH 7.6), 5×Denhardt's solution, 10% dextran sulfate, and 20 μg/ml denatured shearedsalmon sperm DNA; hybridization in the same buffer for 18 to 20 hours;and washing of filters in 1× SSC at about 37° C. for 1 hour.

[0025] Isolation, Production, Expression, and Mis-Expression of PIBNucleic Acids and Polypeptides

[0026] PIB nucleic acids and polypeptides, useful for identifying andtesting agents that modulate PIB function and for other applicationsrelated to the involvement of PIB in the p53 pathway. PIB nucleic acidsand derivatives and orthologs thereof may be obtained using anyavailable method. For instance, techniques for isolating cDNA or genomicDNA sequences of interest by screening DNA libraries or by usingpolymerase chain reaction (PCR) are well known in the art. In general,the particular use for the protein will dictate the particulars ofexpression, production, and purification methods. For instance,production of proteins for use in screening for modulating agents mayrequire methods that preserve specific biological activities of theseproteins, whereas production of proteins for antibody generation mayrequire structural integrity of particular epitopes. Expression ofproteins to be purified for screening or antibody production may requirethe addition of specific tags (e.g., generation of fusion proteins).Overexpression of a PIB protein for assays used to assess PIB function,such as involvement in cell cycle regulation or hypoxic response, mayrequire expression in eukaryotic cell lines capable of these cellularactivities. Techniques for the expression, production, and purificationof proteins are well known in the art; any suitable means therefore maybe used (e.g., Higgins S J and Hames B D (eds.) Protein Expression: APractical Approach, Oxford University Press Inc., New York 1999;Stanbury P F et al., Principles of Fermentation Technology, 2^(nd)edition, Elsevier Science, New York, 1995; Doonan S (ed.) ProteinPurification Protocols, Humana Press, New Jersey, 1996; Coligan J E etal, Current Protocols in Protein Science (eds.), 1999, John Wiley &Sons, New York). In particular embodiments, recombinant PIB is expressedin a cell line known to have defective p53 function (e.g. SAOS-2osteoblasts, H1299 lung cancer cells, C33A and HT3 cervical cancercells, HT-29 and DLD-1 colon cancer cells, among others, available fromAmerican Type Culture Collection (ATCC), Manassas, Va.). The recombinantcells are used in cell-based screening assay systems of the invention,as described further below.

[0027] The nucleotide sequence encoding a PIB polypeptide can beinserted into any appropriate expression vector. The necessarytranscriptional and translational signals, including promoter/enhancerelement, can derive from the native PIB gene and/or its flanking regionsor can be heterologous. A variety of host-vector expression systems maybe utilized, such as mammalian cell systems infected with virus (e.g.vaccinia virus, adenovirus, etc.); insect cell systems infected withvirus (e.g. baculovirus); microorganisms such as yeast containing yeastvectors, or bacteria transformed with bacteriophage, plasmid, or cosmidDNA. A host cell strain that modulates the expression of, modifies,and/or specifically processes the gene product may be used.

[0028] To detect expression of the PIB gene product, the expressionvector can comprise a promoter operably linked to a PIB gene nucleicacid, one or more origins of replication, and, one or more selectablemarkers (e.g. thymidine kinase activity, resistance to antibiotics,etc.). Alternatively, recombinant expression vectors can be identifiedby assaying for the expression of the PIB gene product based on thephysical or functional properties of the PIB protein in in vitro assaysystems (e.g. immunoassays).

[0029] The PIB protein, fragment, or derivative may be optionallyexpressed as a fusion, or chimeric protein product (i.e. it is joinedvia a peptide bond to a heterologous protein sequence of a differentprotein), for example to facilitate purification or detection. Achimeric product can be made by ligating the appropriate nucleic acidsequences encoding the desired amino acid sequences to each other usingstandard methods and expressing the chimeric product. A chimeric productmay also be made by protein synthetic techniques, e.g. by use of apeptide synthesizer (Hunkapiller et al., Nature

[0030] 310:105-111).

[0031] Once a recombinant cell that expresses the PIB gene sequence isidentified, the gene product can be isolated and purified using standardmethods (e.g. ion exchange, affinity, and gel exclusion chromatography;centrifugation; differential solubility; electrophoresis, citepurification reference). Alternatively, native PIB proteins can bepurified from natural sources, by standard methods (e.g. immunoaffinitypurification). Once a protein is obtained, it may be quantified and itsactivity measured by appropriate methods, such as immunoassay, bioassay,or other measurements of physical properties, such as crystallography.

[0032] The methods of this invention may also use cells that have beenengineered for altered expression (mis-expression) of PIB or other genesassociated with the p53 pathway. As used herein, mis-expressionencompasses ectopic expression, over-expression, under-expression, andnon-expression (e.g. by gene knock-out or blocking expression that wouldotherwise normally occur).

[0033] Genetically Modified Animals

[0034] Animal models that have been genetically modified to alter PIBexpression may be used in in vivo assays to test for activity of acandidate p53 modulating agent, or to further assess the role of PIB ina p53 pathway process such as apoptosis or cell proliferation.Preferably, the altered PIB expression results in a detectablephenotype, such as decreased or increased levels of cell proliferation,angiogenesis, or apoptosis compared to control animals having normal PIBexpression. The genetically modified animal may additionally havealtered p53 expression (e.g. p53 knockout). Preferred geneticallymodified animals are mammals such as primates, rodents (preferablymice), cows, horses, goats, sheep, pigs, dogs and cats. Preferrednon-mammalian species include zebrafish, C. elegans, and Drosophila.Preferred genetically modified animals are transgenic animals having aheterologous nucleic acid sequence present as an extrachromosomalelement in a portion of its cells, i.e. mosaic animals (see, forexample, techniques described by Jakobovits, 1994, Curr. Biol.4:761-763.) or stably integrated into its germ line DNA (i.e., in thegenomic sequence of most or all of its cells). Heterologous nucleic acidis introduced into the germ line of such transgenic animals by geneticmanipulation of, for example, embryos or embryonic stem cells of thehost animal.

[0035] Methods of making transgenic animals are well-known in the art(for transgenic mice see Brinster et al., Proc. Nat. Acad. Sci. USA 82:4438-4442 (1985), U.S. Pat. Nos. 4,736,866 and 4,870,009, both by Lederet al., U.S. Pat. No. 4,873,191 by Wagner et al., and Hogan, B.,Manipulating the Mouse Embryo, Cold Spring Harbor Laboratory Press, ColdSpring Harbor, N.Y., (1986); for particle bombardment see U.S. Pat. No.,4,945,050, by Sandford et al.; for transgenic Drosophila see Rubin andSpradling, Science (1982) 218:348-53 and U.S. Pat. No. 4,670,388; fortransgenic insects see Berghammer A. J. et al., A Universal Marker forTransgenic Insects (1999) Nature 402:370-371; for transgenic Zebrafishsee Lin S., Transgenic Zebrafish, Methods Mol Biol.(2000);136:375-3830); for microinjection procedures for fish, amphibianeggs and birds see Houdebine and Chourrout, Experientia (1991)47:897-905; for transgenic rats see Hammer et al., Cell (1990)63:1099-1112; and for culturing of embryonic stem (ES) cells and thesubsequent production of transgenic animals by the introduction of DNAinto ES cells using methods such as electroporation, calciumphosphate/DNA precipitation and direct injection see, e.g.,Teratocarcinomas and Embryonic Stem Cells, A Practical Approach, E. J.Robertson, ed., IRL Press (1987)). Clones of the nonhuman transgenicanimals can be produced according to available methods (see Wilmut, I.et al. (1997) Nature 385:810-813; and PCT International Publication Nos.WO 97/07668 and WO 97/07669).

[0036] In one embodiment, the transgenic animal is a “knock-out” animalhaving a heterozygous or homozygous alteration in the sequence of anendogenous PIB gene that results in a decrease of PIB function,preferably such that PIB expression is undetectable or insignificant.Knock-out animals are typically generated by homologous recombinationwith a vector comprising a transgene having at least a portion of thegene to be knocked out. Typically a deletion, addition or substitutionhas been introduced into the transgene to functionally disrupt it. Thetransgene can be a human gene (e.g., from a human genomic clone) butmore preferably is an ortholog of the human gene derived from thetransgenic host species. For example, a mouse PIB gene is used toconstruct a homologous recombination vector suitable for altering anendogenous PIB gene in the mouse genome. Detailed methodologies forhomologous recombination in mice are available (see Capecchi, Science(1989) 244:1288-1292; Joyner et al., Nature (1989) 338:153-156).Procedures for the production of non-rodent transgenic mammals and otheranimals are also available (Houdebine and Chourrout, supra; Pursel etal., Science (1989) 244:1281-1288; Simms et al., Bio/Technology (1988)6:179-183). In a preferred embodiment, knock-out animals, such as miceharboring a knockout of a specific gene, may be used to produceantibodies against the human counterpart of the gene that has beenknocked out (Claesson M H et al., (1994) Scan J Immunol 40:257-264;Declerck P J et al., (1995) J Biol Chem. 270:8397-400).

[0037] In another embodiment, the transgenic animal is a “knock-in”animal having an alteration in its genome that results in alteredexpression (e.g., increased (including ectopic) or decreased expression)of the PIB gene, e.g., by introduction of additional copies of PIB, orby operatively inserting a regulatory sequence that provides for alteredexpression of an endogenous copy of the PIB gene. Such regulatorysequences include inducible, tissue-specific, and constitutive promotersand enhancer elements. The knock-in can be homozygous or heterozygous.

[0038] Transgenic nonhuman animals can also be produced that containselected systems allowing for regulated expression of the transgene. Oneexample of such a system that may be produced is the cre/loxPrecombinase system of bacteriophage P1 (Lakso et al., PNAS (1992)89:6232-6236; U.S. Pat. No. 4,959,317). If a cre/loxP recombinase systemis used to regulate expression of the transgene, animals containingtransgenes encoding both the Cre recombinase and a selected protein arerequired. Such animals can be provided through the construction of“double” transgenic animals, e.g., by mating two transgenic animals, onecontaining a transgene encoding a selected protein and the othercontaining a transgene encoding a recombinase. Another example of arecombinase system is the FLP recombinase system of Saccharomycescerevisiae (O'Gorman et al. (1991) Science 251:1351-1355; U.S. Pat. No.5,654,182). In a preferred embodiment, both Cre-LoxP and Flp-Frt areused in the same system to regulate expression of the transgene, and forsequential deletion of vector sequences in the same cell (Sun X et al(2000) Nat Genet 25:83-6).

[0039] The genetically modified animals can be used in genetic studiesto further elucidate the p53 pathway, as animal models of disease anddisorders implicating defective p53 function, and for in vivo testing ofcandidate therapeutic agents, such as those identified in screensdescribed below. The candidate therapeutic agents are administered to agenetically modified animal having altered PIB function and phenotypicchanges are compared with appropriate control animals such asgenetically modified animals that receive placebo treatment, and/oranimals with unaltered PIB expression that receive candidate therapeuticagent.

[0040] In addition to the above-described genetically modified animalshaving altered PIB function, animal models having defective p53 function(and otherwise normal PIB function), can be used in the methods of thepresent invention. For example, a p53 knockout mouse can be used toassess, in vivo, the activity of a candidate p53 modulating agentidentified in one of the in vitro assays described below. p53 knockoutmice are described in the literature (Jacks et al., Nature2001;410:1111-1116, 1043-1044; Donehower et al., supra). Preferably, thecandidate p53 modulating agent when administered to a model system withcells defective in p53 function, produces a detectable phenotypic changein the model system indicating that the p53 function is restored, i.e.,the cells exhibit normal cell cycle progression.

[0041] Modulating Agents

[0042] The invention provides methods to identify agents that interactwith and/or modulate the function of PIB and/or the p53 pathway. Suchagents are useful in a variety of diagnostic and therapeuticapplications associated with the p53 pathway, as well as in furtheranalysis of the PIB protein and its contribution to the p53 pathway.Accordingly, the invention also provides methods for modulating the p53pathway comprising the step of specifically modulating PIB activity byadministering a PIB-interacting or -modulating agent.

[0043] In a preferred embodiment, PIB-modulating agents inhibit orenhance PIB activity or otherwise affect normal PIB function, includingtranscription, protein expression, protein localization, and cellular orextra-cellular activity. In a further preferred embodiment, thecandidate p53 pathway-modulating agent specifically modulates thefunction of the PIB. The phrases “specific modulating agent”,“specifically modulates”, etc., are used herein to refer to modulatingagents that directly bind to the PIB polypeptide or nucleic acid, andpreferably inhibit, enhance, or otherwise alter, the function of thePIB. The term also encompasses modulating agents that alter theinteraction of the PIB with a binding partner or substrate (e.g. bybinding to a binding partner of a PIB, or to a protein/binding partnercomplex, and inhibiting function).

[0044] Preferred PIB-modulating agents include small molecule compounds;PIB-interacting proteins, including antibodies and otherbiotherapeutics; and nucleic acid modulators such as antisense and RNAinhibitors. The modulating agents may be formulated in pharmaceuticalcompositions, for example, as compositions that may comprise otheractive ingredients, as in combination therapy, and/or suitable carriersor excipients. Techniques for formulation and administration of thecompounds may be found in “Remington's Pharmaceutical Sciences” MackPublishing Co., Easton, Pa., 19^(th) edition.

[0045] Small Molecule Modulators

[0046] Small molecules, are often preferred to modulate function ofproteins with enzymatic function, and/or containing protein interactiondomains. Chemical agents, referred to in the art as “small molecule”compounds are typically organic, non-peptide molecules, having amolecular weight less than 10,000, preferably less than 5,000, morepreferably less than 1,000, and most preferably less than 500. Thisclass of modulators includes chemically synthesized molecules, forinstance, compounds from combinatorial chemical libraries. Syntheticcompounds may be rationally designed or identified based on known orinferred properties of the PIB protein or may be identified by screeningcompound libraries. Alternative appropriate modulators of this class arenatural products, particularly secondary metabolites from organisms suchas plants or fungi, which can also be identified by screening compoundlibraries for PIB-modulating activity. Methods for generating andobtaining compounds are well known in the art (Schreiber S L, Science(2000) 151: 1964-1969; Radmann J and Gunther J, Science

[0047] 151:1947-1948).

[0048] Small molecule modulators identified from screening assays, asdescribed below, can be used as lead compounds from which candidateclinical compounds may be designed, optimized, and synthesized. Suchclinical compounds may have utility in treating pathologies associatedwith the p53 pathway. The activity of candidate small moleculemodulating agents may be improved several-fold through iterativesecondary functional validation, as further described below, structuredetermination, and candidate modulator modification and testing.Additionally, candidate clinical compounds are generated with specificregard to clinical and pharmacological properties. For example, thereagents may be derivatized and re-screened using in vitro and in vivoassays to optimize activity and minimize toxicity for pharmaceuticaldevelopment.

[0049] Protein Modulators

[0050] Specific PIB-interacting proteins are useful in a variety ofdiagnostic and therapeutic applications related to the p53 pathway andrelated disorders, as well as in validation assays for otherPIB-modulating agents. In a preferred embodiment, PIB-interactingproteins affect normal PIB function, including transcription, proteinexpression, protein localization, and cellular or extra-cellularactivity. In another embodiment, PIB-interacting proteins are useful indetecting and providing information about the function of PIB proteins,as is relevant to p53 related disorders, such as cancer (e.g., fordiagnostic means).

[0051] An PIB-interacting protein may be endogenous, i.e. one thatnaturally interacts genetically or biochemically with a PIB, such as amember of the PIB pathway that modulates PIB expression, localization,and/or activity. PIB-modulators include dominant negative forms ofPIB-interacting proteins and of PIB proteins themselves. Yeasttwo-hybrid and variant screens offer preferred methods for identifyingendogenous PIB-interacting proteins (Finley, R. L. et al. (1996) in DNACloning-Expression Systems: A Practical Approach, eds. Glover D. & HamesB. D (Oxford University Press, Oxford, England), pp. 169-203; Fashema SF et al., Gene (2000) 250: 1-14; Drees B L Curr Opin Chem Biol (1999)3:64-70; Vidal M and Legrain P Nucleic Acids Res (1999) 27:919-29; andU.S. Pat. No. 5,928,868). Mass spectrometry is an alternative preferredmethod for the elucidation of protein complexes (reviewed in, e.g.,Pandley A and Mann M, Nature (2000) 405:837-846; Yates J R 3^(rd),Trends Genet (2000) 16:5-8).

[0052] An PIB-interacting protein may be an exogenous protein, such as aPIB-specific antibody or a T-cell antigen receptor (see, e.g., Harlowand Lane (1988) Antibodies, A Laboratory Manual, Cold Spring HarborLaboratory; Harlow and Lane (1999) Using antibodies: a laboratorymanual. Cold Spring Harbor, N.Y.: Cold Spring Harbor Laboratory Press).PIB antibodies are further discussed below.

[0053] In preferred embodiments, a PIB-interacting protein specificallybinds a PIB protein. In alternative preferred embodiments, aPIB-modulating agent binds a PIB substrate, binding partner, orcofactor.

[0054] Antibodies

[0055] In another embodiment, the protein modulator is a PIB specificantibody agonist or antagonist.

[0056] The antibodies have therapeutic and diagnostic utilities, and canbe used in screening assays to identify PIB modulators. The antibodiescan also be used in dissecting the portions of the PIB pathwayresponsible for various cellular responses and in the general processingand maturation of the PIB.

[0057] Antibodies that specifically bind PIB polypeptides can begenerated using known methods. Preferably the antibody is specific to amammalian ortholog of PIB polypeptide, and more preferably, to humanPIB. Antibodies may be polyclonal, monoclonal (mAbs), humanized orchimeric antibodies, single chain antibodies, Fab fragments,F(ab′).sub.2 fragments, fragments produced by a FAb expression library,anti-idiotypic (anti-Id) antibodies, and epitope-binding fragments ofany of the above. Epitopes of PIB which are particularly antigenic canbe selected, for example, by routine screening of PIB polypeptides forantigenicity or by applying a theoretical method for selecting antigenicregions of a protein (Hopp and Wood (1981), Proc. Nati. Acad. Sci.U.S.A. 78:3824-28; Hopp and Wood, (1983) Mol. Immunol. 20:483-89;Sutcliffe et al., (1983)Science 219:660-66) to the amino acid sequenceshown in any of SEQ ID NOs:10, 11, 12, 13, or 14. Monoclonal antibodieswith affinities of 10⁸ M⁻¹ preferably 10⁹ M⁻¹ to 10¹⁰ M⁻¹, or strongercan be made by standard procedures as described (Harlow and Lane, supra;Goding (1986) Monoclonal Antibodies: Principles and Practice (2d ed)Academic Press, New York; and U.S. Pat. Nos. 4,381,292; 4,451,570; and4,618,577). Antibodies may be generated against crude cell extracts ofPIB or substantially purified fragments thereof. If PIB fragments areused, they preferably comprise at least 10, and more preferably, atleast 20 contiguous amino acids of a PIB protein. In a particularembodiment, PIB-specific antigens and/or immunogens are coupled tocarrier proteins that stimulate the immune response. For example, thesubject polypeptides are covalently coupled to the keyhole limpethemocyanin (KLH) carrier, and the conjugate is emulsified in Freund'scomplete adjuvant, which enhances the immune response. An appropriateimmune system such as a laboratory rabbit or mouse is immunizedaccording to conventional protocols.

[0058] The presence of PIB-specific antibodies is assayed by anappropriate assay such as a solid phase enzyme-linked immunosorbantassay (ELISA) using immobilized corresponding PIB polypeptides. Otherassays, such as radioimmunoassays or fluorescent assays might also beused.

[0059] Chimeric antibodies specific to PIB polypeptides can be made thatcontain different portions from different animal species. For instance,a human immunoglobulin constant region may be linked to a variableregion of a murine mAb, such that the antibody derives its biologicalactivity from the human antibody, and its binding specificity from themurine fragment. Chimeric antibodies are produced by splicing togethergenes that encode the appropriate regions from each species (Morrison etal., Proc. Natl. Acad. Sci. (1984) 81:6851-6855; Neuberger et al.,Nature (1984) 312:604-608; Takeda et al., Nature (1985) 31:452-454).Humanized antibodies, which are a form of chimeric antibodies, can begenerated by grafting complementary-determining regions (CDRs) (Carlos,T. M., J. M. Harlan. 1994. Blood 84:2068-2101) of mouse antibodies intoa background of human framework regions and constant regions byrecombinant DNA technology (Riechmann L M, et al., 1988 Nature 323:323-327). Humanized antibodies contain ˜10% murine sequences and ˜90%human sequences, and thus further reduce or eliminate immunogenicity,while retaining the antibody specificities (Co MS, and Queen C. 1991Nature 351: 501-501; Morrison SL. 1992 Ann. Rev. Immun. 10:239-265).Humanized antibodies and methods of their production are well-known inthe art (U.S. Pat. Nos. 5,530,101, 5,585,089, 5,693,762, and 6,180,370).

[0060] PIB-specific single chain antibodies which are recombinant,single chain polypeptides formed by linking the heavy and light chainfragments of the Fv regions via an amino acid bridge, can be produced bymethods known in the art (U.S. Pat. No. 4,946,778; Bird, Science (1988)242:423-426; Huston et al., Proc. Natl. Acad. Sci. USA(1988)85:5879-5883; and Ward et al., Nature (1989) 334:544-546).

[0061] Other suitable techniques for antibody production involve invitro exposure of lymphocytes to the antigenic polypeptides oralternatively to selection of libraries of antibodies in phage orsimilar vectors (Huse et al., Science (1989) 246:1275-1281). As usedherein, T-cell antigen receptors are included within the scope ofantibody modulators (Harlow and Lane, 1988, supra).

[0062] The polypeptides and antibodies of the present invention may beused with or without modification. Frequently, antibodies will belabeled by joining, either covalently or non-covalently, a substancethat provides for a detectable signal, or that is toxic to cells thatexpress the targeted protein (Menard S, et al., Int J. Biol Markers(1989) 4:131-134). A wide variety of labels and conjugation techniquesare known and are reported extensively in both the scientific and patentliterature. Suitable labels include radionuclides, enzymes, substrates,cofactors, inhibitors, fluorescent moieties, fluorescent emittinglanthanide metals, chemiluminescent moieties, bioluminescent moieties,magnetic particles, and the like (U.S. Pat. Nos. 3,817,837; 3,850,752;3,939,350; 3,996,345; 4,277,437; 4,275,149; and 4,366,241). Also,recombinant immunoglobulins may be produced (U.S. Pat. No. 4,816,567).Antibodies to cytoplasmic polypeptides may be delivered and reach theirtargets by conjugation with membrane-penetrating toxin proteins (U.S.Pat. No. 6,086,900).

[0063] When used therapeutically in a patient, the antibodies of thesubject invention are typically administered parenterally, when possibleat the target site, or intravenously. The therapeutically effective doseand dosage regimen is determined by clinical studies. Typically, theamount of antibody administered is in the range of about 0.1 mg/kg—toabout 10 mg/kg of patient weight. For parenteral administration, theantibodies are formulated in a unit dosage injectable form (e.g.,solution, suspension, emulsion) in association with a pharmaceuticallyacceptable vehicle. Such vehicles are inherently nontoxic andnon-therapeutic. Examples are water, saline, Ringer's solution, dextrosesolution, and 5% human serum albumin. Nonaqueous vehicles such as fixedoils, ethyl oleate, or liposome carriers may also be used. The vehiclemay contain minor amounts of additives, such as buffers andpreservatives, which enhance isotonicity and chemical stability orotherwise enhance therapeutic potential. The antibodies' concentrationsin such vehicles are typically in the range of about 1 mg/ml to about 10mg/ml. Immunotherapeutic methods are further described in the literature(U.S. Pat. No. 5,859,206; WO0073469).

[0064] Nucleic Acid Modulators

[0065] Other preferred PIB-modulating agents comprise nucleic acidmolecules, such as antisense oligomers or double stranded RNA (dsRNA),which generally inhibit PIB activity. Preferred nucleic acid modulatorsinterfere with the function of the PIB nucleic acid such as DNAreplication, transcription, translocation of the PIB RNA to the site ofprotein translation, translation of protein from the PIB RNA, splicingof the PIB RNA to yield one or more mRNA species, or catalytic activitywhich may be engaged in or facilitated by the PIB RNA.

[0066] In one embodiment, the antisense oligomer is an oligonucleotidethat is sufficiently complementary to a PIB mRNA to bind to and preventtranslation, preferably by binding to the 5′ untranslated region.PIB-specific antisense oligonucleotides, preferably range from at least6 to about 200 nucleotides. In some embodiments the oligonucleotide ispreferably at least 10, 15, or 20 nucleotides in length. In otherembodiments, the oligonucleotide is preferably less than 50, 40, or 30nucleotides in length. The oligonucleotide can be DNA or RNA or achimeric mixture or derivatives or modified versions thereof,single-stranded or double-stranded. The oligonucleotide can be modifiedat the base moiety, sugar moiety, or phosphate backbone. Theoligonucleotide may include other appending groups such as peptides,agents that facilitate transport across the cell membrane,hybridization-triggered cleavage agents, and intercalating agents.

[0067] In another embodiment, the antisense oligomer is a phosphothioatemorpholino oligomer (PMO). PMOs are assembled from four differentmorpholino subunits, each of which contain one of four genetic bases (A,C, G, or T) linked to a six-membered morpholine ring. Polymers of thesesubunits are joined by non-ionic phosphodiamidate intersubunit linkages.Details of how to make and use PMOs and other antisense oligomers arewell known in the art (e.g. see WO99/18193; Probst JC, AntisenseOligodeoxynucleotide and Ribozyme Design, Methods. (2000) 22(3):271-281;Summerton J, and Weller D. 1997 Antisense Nucleic Acid Drug Dev.:7:187-95; U.S. Pat. No. 5,235,033; and U.S. Pat. No. 5,378,841).

[0068] Alternative preferred PIB nucleic acid modulators aredouble-stranded RNA species mediating RNA interference (RNAi). RNAi isthe process of sequence-specific, post-transcriptional gene silencing inanimals and plants, initiated by double-stranded RNA (dsRNA) that ishomologous in sequence to the silenced gene. Methods relating to the useof RNAi to silence genes in C. elegans, Drosophila, plants, and humansare known in the art (Fire A, et al., 1998 Nature 391:806-811; Fire, A.Trends Genet. 15, 358-363 (1999); Sharp, P. A. RNA interference 2001.Genes Dev. 15, 485-490 (2001); Hammond, S. M., et al., Nature Rev.Genet. 2, 110-1119 (2001); Tuschl, T. Chem. Biochem. 2, 239-245 (2001);Hamilton, A. et al., Science 286, 950-952 (1999); Hammond, S. M., etal., Nature 404, 293-296 (2000); Zamore, P. D., et al., Cell 101, 25-33(2000); Bernstein, E., et al., Nature 409, 363-366 (2001); Elbashir, S.M., et al., Genes Dev. 15, 188-200 (2001); WO0129058; WO9932619;Elbashir S M, et al., 2001 Nature 411:494-498).

[0069] Nucleic acid modulators are commonly used as research reagents,diagnostics, and therapeutics. For example, antisense oligonucleotides,which are able to inhibit gene expression with exquisite specificity,are often used to elucidate the function of particular genes (see, forexample, U.S. Pat. No. 6,165,790). Nucleic acid modulators are alsoused, for example, to distinguish between functions of various membersof a biological pathway. For example, antisense oligomers have beenemployed as therapeutic moieties in the treatment of disease states inanimals and man and have been demonstrated in numerous clinical trialsto be safe and effective (Milligan J F, et al, Current Concepts inAntisense Drug Design, J Med Chem. (1993) 36:1923-1937; Tonkinson J L etal., Antisense Oligodeoxynucleotides as Clinical Therapeutic Agents,Cancer Invest. (1996) 14:54-65). Accordingly, in one aspect of theinvention, a PIB-specific nucleic acid modulator is used in an assay tofurther elucidate the role of the PIB in the p53 pathway, and/or itsrelationship to other members of the pathway. In another aspect of theinvention, a PIB-specific antisense oligomer is used as a therapeuticagent for treatment of p53-related disease states.

[0070] Assay Systems

[0071] The invention provides assay systems and screening methods foridentifying specific modulators of PIB activity. As used herein, an“assay system” encompasses all the components required for performingand analyzing results of an assay that detects and/or measures aparticular event. In general, primary assays are used to identify orconfirm a modulator's specific biochemical or molecular effect withrespect to the PIB nucleic acid or protein. In general, secondary assaysfurther assess the activity of a PIB modulating agent identified by aprimary assay and may confirm that the modulating agent affects PIB in amanner relevant to the p53 pathway. In some cases, PIB modulators willbe directly tested in a secondary assay.

[0072] In a preferred embodiment, the screening method comprisescontacting a suitable assay system comprising a PIB polypeptide with acandidate agent under conditions whereby, but for the presence of theagent, the system provides a reference activity (e.g. phosphataseactivity), which is based on the particular molecular event thescreening method detects. A statistically significant difference betweenthe agent-biased activity and the reference activity indicates that thecandidate agent modulates PIB activity, and hence the p53 pathway.

[0073] Primary Assays

[0074] The type of modulator tested generally determines the type ofprimary assay.

[0075] Primary Assays for Small Molecule Modulators

[0076] For small molecule modulators, screening assays are used toidentify candidate modulators. Screening assays may be cell-based or mayuse a cell-free system that recreates or retains the relevantbiochemical reaction of the target protein (reviewed in Sittampalam G Set al., Curr Opin Chem Biol (1997) 1:384-91 and accompanyingreferences). As used herein the term “cell-based” refers to assays usinglive cells, dead cells, or a particular cellular fraction, such as amembrane, endoplasmic reticulum, or mitochondrial fraction. The term“cell free” encompasses assays using substantially purified protein(either endogenous or recombinantly produced), partially purified orcrude cellular extracts. Screening assays may detect a variety ofmolecular events, including protein-DNA interactions, protein-proteininteractions (e.g., receptor-ligand binding), transcriptional activity(e.g., using a reporter gene), enzymatic activity (e.g., via a propertyof the substrate), activity of second messengers, immunogenicty andchanges in cellular morphology or other cellular characteristics.Appropriate screening assays may use a wide range of detection methodsincluding fluorescent, radioactive, colorimetric, spectrophotometric,and amperometric methods, to provide a read-out for the particularmolecular event detected.

[0077] Cell-based screening assays usually require systems forrecombinant expression of PIB and any auxiliary proteins demanded by theparticular assay. Appropriate methods for generating recombinantproteins produce sufficient quantities of proteins that retain theirrelevant biological activities and are of sufficient purity to optimizeactivity and assure assay reproducibility. Yeast two-hybrid and variantscreens, and mass spectrometry provide preferred methods for determiningprotein-protein interactions and elucidation of protein complexes. Incertain applications, when PIB-interacting proteins are used in screensto identify small molecule modulators, the binding specificity of theinteracting protein to the PIB protein may be assayed by various knownmethods such as substrate processing (e.g. ability of the candidatePIB-specific binding agents to function as negative effectors inPIB-expressing cells), binding equilibrium constants (usually at leastabout 10⁷ M⁻¹, preferably at least about 10⁸ M⁻¹, more preferably atleast about 10⁹ M⁻¹), and immunogenicity (e.g. ability to elicit PIBspecific antibody in a heterologous host such as a mouse, rat, goat orrabbit). For enzymes and receptors, binding may be assayed by,respectively, substrate and ligand processing.

[0078] The screening assay may measure a candidate agent's ability tospecifically bind to or modulate activity of a PIB polypeptide, a fusionprotein thereof, or to cells or membranes bearing the polypeptide orfusion protein. The PIB polypeptide can be full length or a fragmentthereof that retains functional PIB activity. The PIB polypeptide may befused to another polypeptide, such as a peptide tag for detection oranchoring, or to another tag. The PIB polypeptide is preferably humanPIB, or is an ortholog or derivative thereof as described above. In apreferred embodiment, the screening assay detects candidate agent-basedmodulation of PIB interaction with a binding target, such as anendogenous or exogenous protein or other substrate that has PIB-specific binding activity, and can be used to assess normal PIB genefunction.

[0079] Suitable assay formats that may be adapted to screen for PIBmodulators are known in the art. Preferred screening assays are highthroughput or ultra high throughput and thus provide automated,cost-effective means of screening compound libraries for lead compounds(Fernandes P B, Curr Opin Chem Biol (1998) 2:597-603; Sundberg S A, CurrOpin Biotechnol 2000, 11:47-53). In one preferred embodiment, screeningassays uses fluorescence technologies, including fluorescencepolarization, time-resolved fluorescence, and fluorescence resonanceenergy transfer. These systems offer means to monitor protein-protein orDNA-protein interactions in which the intensity of the signal emittedfrom dye-labeled molecules depends upon their interactions with partnermolecules (e.g., Selvin PR, Nat Struct Biol (2000) 7:730-4; Fernandes PB, supra; Hertzberg R P and Pope A J, Curr Opin Chem Biol (2000)4:445-451).

[0080] A variety of suitable assay systems may be used to identifycandidate PIB and p53 pathway modulators (e.g. U.S. Pat. Nos. 5,550,019and 6,133,437 (apoptosis assays); U.S. Pat. No. 6,020,135 (p53modulation), U.S. Pat. No. 6,114,132 (phosphatase and protease assays),among others). Specific preferred assays are described in more detailbelow.

[0081] Phosphatase assays. Protein phosophatases catalyze the removal ofa gamma phosphate from a serine, threonine or tyrosine residue in aprotein substrate. Since phosphatases act in opposition to kinases,appropriate assays measure the same parameters as kinase assays. In oneexample, the dephosphorylation of a fluorescently labeled peptidesubstrate allows trypsin cleavage of the substrate, which in turnrenders the cleaved substrate significantly more fluorescent (NishikataM et al., Biochem J

[0082] 343:35-391). In another example, fluorescence polarization (FP),a solution-based, homogeneous technique requiring no immobilization orseparation of reaction components, is used to develop high throughputscreening (HTS) assays for protein phosphatases. This assay uses directbinding of the phosphatase with the target, and increasingconcentrations of target-phosphatase increase the rate ofdephosphorylation, leading to a change in polarization (Parker G J etal., (2000) J Biomol Screen 5:77-88).

[0083] Apoptosis assays. Assays for apoptosis may be performed byterminal deoxynucleotidyl transferase-mediated digoxigenin-11-dUTP nickend labeling (TUNEL) assay. The TUNEL assay is used to measure nuclearDNA fragmentation characteristic of apoptosis (Lazebnik et al., 1994,Nature 371, 346), by following the incorporation of fluorescein-dUTP(Yonehara et al., 1989, J. Exp. Med. 169, 1747). Apoptosis may furtherbe assayed by acridine orange staining of tissue culture cells (Lucas,R., et al., 1998, Blood 15:4730-41). An apoptosis assay system maycomprise a cell that expresses a PIB, and that optionally has defectivep53 function (e.g. p53 is over-expressed or under-expressed relative towild-type cells). A test agent can be added to the apoptosis assaysystem and changes in induction of apoptosis relative to controls whereno test agent is added, identify candidate p53 modulating agents. Insome embodiments of the invention, an apoptosis assay may be used as asecondary assay to test a candidate p53 modulating agents that isinitially identified using a cell-free assay system. An apoptosis assaymay also be used to test whether PIB function plays a direct role inapoptosis. For example, an apoptosis assay may be performed on cellsthat over- or under-express PIB relative to wild type cells. Differencesin apoptotic response compared to wild type cells suggests that the PIBplays a direct role in the apoptotic response. Apoptosis assays aredescribed further in U.S. Pat. No. 6,133,437.

[0084] Cell proliferation and cell cycle assays. Cell proliferation maybe assayed via bromodeoxyuridine (BRDU) incorporation. This assayidentifies a cell population undergoing DNA synthesis by incorporationof BRDU into newly-synthesized DNA. Newly-synthesized DNA may then bedetected using an anti-BRDU antibody (Hoshino et al., 1986, Int. J.Cancer 38, 369; Campana et al., 1988, J. Immunol. Meth. 107, 79), or byother means.

[0085] Cell Proliferation may also be examined using [³H]-thymidineincorporation (Chen, J., 1996, Oncogene 13:1395-403; Jeoung, J., 1995,J. Biol. Chem. 270:18367-73). This assay allows for quantitativecharacterization of S-phase DNA syntheses. In this assay, cellssynthesizing DNA will incorporate [³H]-thymidine into newly synthesizedDNA. Incorporation can then be measured by standard techniques such asby counting of radioisotope in a scintillation counter (e.g., Beckman LS3800 Liquid Scintillation Counter).

[0086] Cell proliferation may also be assayed by colony formation insoft agar (Sambrook et al., Molecular Cloning, Cold Spring Harbor(1989)). For example, cells transformed with PIB are seeded in soft agarplates, and colonies are measured and counted after two weeksincubation.

[0087] Involvement of a gene in the cell cycle may be assayed by flowcytometry (Gray J W et al. (1986) Int J Radiat Biol Relat Stud Phys ChemMed 49:237-55). Cells transfected with a PIB may be stained withpropidium iodide and evaluated in a flow cytometer (available fromBecton Dickinson).

[0088] Accordingly, a cell proliferation or cell cycle assay system maycomprise a cell that expresses a PIB, and that optionally has defectivep53 function (e.g. p53 is over-expressed or under-expressed relative towild-type cells). A test agent can be added to the assay system andchanges in cell proliferation or cell cycle relative to controls whereno test agent is added, identify candidate p53 modulating agents. Insome embodiments of the invention, the cell proliferation or cell cycleassay may be used as a secondary assay to test a candidate p53modulating agents that is initially identified using another assaysystem such as a cell-free phosphatase assay system. A cellproliferation assay may also be used to test whether PIB function playsa direct role in cell proliferation or cell cycle. For example, a cellproliferation or cell cycle assay may be performed on cells that over-or under-express PIB relative to wild type cells. Differences inproliferation or cell cycle compared to wild type cells suggests thatthe PIB plays a direct role in cell proliferation or cell cycle.

[0089] Angiogenesis. Angiogenesis may be assayed using various humanendothelial cell systems, such as umbilical vein, coronary artery, ordermal cells. Suitable assays include Alamar Blue based assays(available from Biosource International) to measure proliferation;migration assays using fluorescent molecules, such as the use of BectonDickinson Falcon HTS FluoroBlock cell culture inserts to measuremigration of cells through membranes in presence or absence ofangiogenesis enhancer or suppressors; and tubule formation assays basedon the formation of tubular structures by endothelial cells on Matrigel®(Becton Dickinson). Accordingly, an angiogenesis assay system maycomprise a cell that expresses a PIB, and that optionally has defectivep53 function (e.g. p53 is over-expressed or under-expressed relative towild-type cells). A test agent can be added to the angiogenesis assaysystem and changes in angiogenesis relative to controls where no testagent is added, identify candidate p53 modulating agents. In someembodiments of the invention, the angiogenesis assay may be used as asecondary assay to test a candidate p53 modulating agents that isinitially identified using another assay system. An angiogenesis assaymay also be used to test whether PIB function plays a direct role incell proliferation. For example, an angiogenesis assay may be performedon cells that over- or under-express PIB relative to wild type cells.Differences in angiogenesis compared to wild type cells suggests thatthe PIB plays a direct role in angiogenesis.

[0090] Hypoxic induction. The alpha subunit of the transcription factor,hypoxia inducible factor-1 (HIF-1), is upregulated in tumor cellsfollowing exposure to hypoxia in vitro. Under hypoxic conditions, HIF-1stimulates the expression of genes known to be important in tumour cellsurvival, such as those encoding glyolytic enzymes and VEGF. Inductionof such genes by hypoxic conditions may be assayed by growing cellstransfected with PIB in hypoxic conditions (such as with 0.1% O2, 5%CO2, and balance N2, generated in a Napco 7001 incubator (PrecisionScientific)) and normoxic conditions, followed by assessment of geneactivity or expression by Taqman®. For example, a hypoxic inductionassay system may comprise a cell that expresses a PIB, and thatoptionally has a mutated p53 (e.g. p53 is over-expressed orunder-expressed relative to wild-type cells). A test agent can be addedto the hypoxic induction assay system and changes in hypoxic responserelative to controls where no test agent is added, identify candidatep53 modulating agents. In some embodiments of the invention, the hypoxicinduction assay may be used as a secondary assay to test a candidate p53modulating agents that is initially identified using another assaysystem. A hypoxic induction assay may also be used to test whether PIBfunction plays a direct role in the hypoxic response. For example, ahypoxic induction assay may be performed on cells that over- orunder-express PIB relative to wild type cells. Differences in hypoxicresponse compared to wild type cells suggests that the PIB plays adirect role in hypoxic induction.

[0091] Cell adhesion. Cell adhesion assays measure adhesion of cells topurified adhesion proteins, or adhesion of cells to each other, inpresence or absence of candidate modulating agents. Cell-proteinadhesion assays measure the ability of agents to modulate the adhesionof cells to purified proteins. For example, recombinant proteins areproduced, diluted to 2.5g/mL in PBS, and used to coat the wells of amicrotiter plate. The wells used for negative control are not coated.Coated wells are then washed, blocked with 1% BSA, and washed again.Compounds are diluted to 2× final test concentration and added to theblocked, coated wells. Cells are then added to the wells, and theunbound cells are washed off. Retained cells are labeled directly on theplate by adding a membrane-permeable fluorescent dye, such ascalcein-AM, and the signal is quantified in a fluorescent microplatereader.

[0092] Cell-cell adhesion assays measure the ability of agents tomodulate binding of cell adhesion proteins with their native ligands.These assays use cells that naturally or recombinantly express theadhesion protein of choice. In an exemplary assay, cells expressing thecell adhesion protein are plated in wells of a multiwell plate. Cellsexpressing the ligand are labeled with a membrane-permeable fluorescentdye, such as BCECF, and allowed to adhere to the monolayers in thepresence of candidate agents. Unbound cells are washed off, and boundcells are detected using a fluorescence plate reader.

[0093] High-throughput cell adhesion assays have also been described. Inone such assay, small molecule ligands and peptides are bound to thesurface of microscope slides using a microarray spotter, intact cellsare then contacted with the slides, and unbound cells are washed off. Inthis assay, not only the binding specificity of the peptides andmodulators against cell lines are determined, but also the functionalcell signaling of attached cells using immunofluorescence techniques insitu on the microchip is measured (Falsey J R et al., Bioconjug Chem.2001 May-Jun;12(3):346-53).

[0094] Primary Assays for Antibody Modulators

[0095] For antibody modulators, appropriate primary assays test is abinding assay that tests the antibody's affinity to and specificity forthe PIB protein. Methods for testing antibody affinity and specificityare well known in the art (Harlow and Lane, 1988, 1999, supra). Theenzyme-linked immunosorbant assay (ELISA) is a preferred method fordetecting PIB-specific antibodies; others include FACS assays,radioimmunoassays, and fluorescent assays.

[0096] Primary Assays for Nucleic Acid Modulators

[0097] For nucleic acid modulators, primary assays may test the abilityof the nucleic acid modulator to inhibit or enhance PIB gene expression,preferably mRNA expression. In general, expression analysis comprisescomparing PIB expression in like populations of cells (e.g., two poolsof cells that endogenously or recombinantly express PIB) in the presenceand absence of the nucleic acid modulator. Methods for analyzing mRNAand protein expression are well known in the art. For instance, Northernblotting, slot blotting, ribonuclease protection, quantitative RT-PCR(e.g., using the TaqMan®, PE Applied Biosystems), or microarray analysismay be used to confirm that PIB mRNA expression is reduced in cellstreated with the nucleic acid modulator (e.g., Current Protocols inMolecular Biology (1994) Ausubel F M et al., eds., John Wiley & Sons,Inc., chapter 4; Freeman W M et al., Biotechniques (1999) 26:112-125;Kallioniemi O P, Ann Med 2001, 33:142-147; Blohm D H and Guiseppi-Elie,A Curr Opin Biotechnol 2001, 12:41-47). Protein expression may also bemonitored. Proteins are most commonly detected with specific antibodiesor antisera directed against either the PIB protein or specificpeptides. A variety of means including Western blotting, ELISA, or insitu detection, are available (Harlow E and Lane D, 1988 and 1999,supra).

[0098] Secondary Assays

[0099] Secondary assays may be used to further assess the activity ofPIB-modulating agent identified by any of the above methods to confirmthat the modulating agent affects PIB in a manner relevant to the p53pathway. As used herein, PIB-modulating agents encompass candidateclinical compounds or other agents derived from previously identifiedmodulating agent. Secondary assays can also be used to test the activityof a modulating agent on a particular genetic or biochemical pathway orto test the specificity of the modulating agent's interaction with PIB.

[0100] Secondary assays generally compare like populations of cells oranimals (e.g., two pools of cells or animals that endogenously orrecombinantly express PIB) in the presence and absence of the candidatemodulator. In general, such assays test whether treatment of cells oranimals with a candidate PIB-modulating agent results in changes in thep53 pathway in comparison to untreated (or mock- or placebo-treated)cells or animals. Certain assays use “sensitized genetic backgrounds”,which, as used herein, describe cells or animals engineered for alteredexpression of genes in the p53 or interacting pathways.

[0101] Cell-Based Assays

[0102] Cell based assays may use a variety of mammalian cell lines knownto have defective p53 function (e.g. SAOS-2 osteoblasts, H1299 lungcancer cells, C33A and HT3 cervical cancer cells, HT-29 and DLD-1 coloncancer cells, among others, available from American Type CultureCollection (ATCC), Manassas, Va.). Cell based assays may detectendogenous p53 pathway activity or may rely on recombinant expression ofp53 pathway components. Any of the aforementioned assays may be used inthis cell-based format. Candidate modulators are typically added to thecell media but may also be injected into cells or delivered by any otherefficacious means.

[0103] Animal Assays

[0104] A variety of non-human animal models of normal or defective p53pathway may be used to test candidate PIB modulators. Models fordefective p53 pathway typically use genetically modified animals thathave been engineered to mis-express (e.g., over-express or lackexpression in) genes involved in the p53 pathway. Assays generallyrequire systemic delivery of the candidate modulators, such as by oraladministration, injection, etc.

[0105] In a preferred embodiment, p53 pathway activity is assessed bymonitoring neovascularization and angiogenesis. Animal models withdefective and normal p53 are used to test the candidate modulator'saffect on PIB in Matrigel® assays. Matrigel® is an extract of basementmembrane proteins, and is composed primarily of laminin, collagen IV,and heparin sulfate proteoglycan. It is provided as a sterile liquid at4° C., but rapidly forms a solid gel at 37 C. Liquid Matrigel® is mixedwith various angiogenic agents, such as bFGF and VEGF, or with humantumor cells which over-express the PIB. The mixture is then injectedsubcutaneously(SC) into female athymic nude mice (Taconic, Germantown,N.Y.) to support an intense vascular response. Mice with Matrigel®pellets may be dosed via oral (PO), intraperitoneal (IP), or intravenous(IV) routes with the candidate modulator. Mice are euthanized 5-12 dayspost-injection, and the Matrigel® pellet is harvested for hemoglobinanalysis (Sigma plasma hemoglobin kit). Hemoglobin content of the gel isfound to correlate the degree of neovascularization in the gel.

[0106] In another preferred embodiment, the effect of the candidatemodulator on PIB is assessed via tumorigenicity assays. In one example,xenograft human tumors are implanted SC into female athymic mice, 6-7week old, as single cell suspensions either from a pre-existing tumor orfrom in vitro culture. The tumors which express the PIB endogenously areinjected in the flank, 1×10⁵ to 1×10⁷ cells per mouse in a volume of 100μL using a 27gauge needle. Mice are then ear tagged and tumors aremeasured twice weekly. Candidate modulator treatment is initiated on theday the mean tumor weight reaches 100 mg. Candidate modulator isdelivered IV, SC, IP, or PO by bolus administration. Depending upon thepharmacokinetics of each unique candidate modulator, dosing can beperformed multiple times per day. The tumor weight is assessed bymeasuring perpendicular diameters with a caliper and calculated bymultiplying the measurements of diameters in two dimensions. At the endof the experiment, the excised tumors maybe utilized for biomarkeridentification or further analyses. For immunohistochemistry staining,xenograft tumors are fixed in 4% paraformaldehyde, 0.1M phosphate, pH7.2, for 6 hours at 4° C., immersed in 30% sucrose in PBS, and rapidlyfrozen in isopentane cooled with liquid nitrogen.

[0107] Diagnostic and Therapeutic Uses

[0108] Specific PIB-modulating agents are useful in a variety ofdiagnostic and therapeutic applications where disease or diseaseprognosis is related to defects in the p53 pathway, such as angiogenic,apoptotic, or cell proliferation disorders. Accordingly, the inventionalso provides methods for modulating the p53 pathway in a cell,preferably a cell pre-determined to have defective p53 function,comprising the step of administering an agent to the cell thatspecifically modulates PIB activity. Preferably, the modulating agentproduces a detectable phenotypic change in the cell indicating that thep53 function is restored, i.e., for example, the cell undergoes normalproliferation or progression through the cell cycle.

[0109] The discovery that PIB is implicated in p53 pathway provides fora variety of methods that can be employed for the diagnostic andprognostic evaluation of diseases and disorders involving defects in thep53 pathway and for the identification of subjects having apredisposition to such diseases and disorders.

[0110] Various expression analysis methods can be used to diagnosewhether PIB expression occurs in a particular sample, including Northernblotting, slot blotting, ribonuclease protection, quantitative RT-PCR,and microarray analysis. (e.g., Current Protocols in Molecular Biology(1994) Ausubel F M et al., eds., John Wiley & Sons, Inc., chapter 4;Freeman W M et al., Biotechniques (1999) 26:112-125; Kallioniemi O P,Ann Med 2001, 33:142-147; Blohm and Guiseppi-Elie, Curr Opin Biotechnol2001, 12:41-47). Tissues having a disease or disorder implicatingdefective p53 signaling that express a PIB, are identified as amenableto treatment with a PIB modulating agent. In a preferred application,the p53 defective tissue overexpresses a PIB relative to normal tissue.For example, a Northern blot analysis of mRNA from tumor and normal celllines, or from tumor and matching normal tissue samples from the samepatient, using full or partial PIB cDNA sequences as probes, candetermine whether particular tumors express or overexpress PIB.Alternatively, the TaqMan® is used for quantitative RT-PCR analysis ofPIB expression in cell lines, normal tissues and tumor samples (PEApplied Biosystems).

[0111] Various other diagnostic methods may be performed, for example,utilizing reagents such as the PIB oligonucleotides, and antibodiesdirected against a PIB, as described above for: (1) the detection of thepresence of PIB gene mutations, or the detection of either over- orunder-expression of PIB mRNA relative to the non-disorder state; (2) thedetection of either an over- or an under-abundance of PIB gene productrelative to the non-disorder state; and (3) the detection ofperturbations or abnormalities in the signal transduction pathwaymediated by PIB.

[0112] Thus, in a specific embodiment, the invention is drawn to amethod for diagnosing a disease in a patient, the method comprising: a)obtaining a biological sample from the patient; b) contacting the samplewith a probe for PIB expression; c) comparing results from step (b) witha control; and d) determining whether step (c) indicates a likelihood ofdisease. Preferably, the disease is cancer, most preferably a cancer asshown in TABLE 1. The probe may be either DNA or protein, including anantibody.

EXAMPLES

[0113] The following experimental section and examples are offered byway of illustration and not by way of limitation.

[0114] I. Drosophila p53 Screen

[0115] The Drosophila p53 gene was overexpressed specifically in thewing using the vestigial margin quadrant enhancer. Increasing quantitiesof Drosophila p53 (titrated using different strength transgenic insertsin 1 or 2 copies) caused deterioration of normal wing morphology frommild to strong, with phenotypes including disruption of pattern andpolarity of wing hairs, shortening and thickening of wing veins,progressive crumpling of the wing and appearance of dark “death”inclusions in wing blade. In a screen designed to identify enhancers andsuppressors of Drosophila p53, homozygous females carrying two copies ofp53 were crossed to 5663 males carrying random insertions of a piggyBactransposon (Fraser M et al., Virology (1985) 145:356-361). Progenycontaining insertions were compared to non-insertion-bearing siblingprogeny for enhancement or suppression of the p53 phenotypes. Sequenceinformation surrounding the piggyBac insertion site was used to identifythe modifier genes. Modifiers of the wing phenotype were identified asmembers of the p53 pathway. CG6805 was an enhancer of the wingphenotype. Human orthologs of the modifiers, are referred to herein asPIB.

[0116] BLAST analysis (Altschul et al., supra) was employed to identifyTargets from Drosophila modifiers. For example, representative sequencesfrom PIB, GI# 4314432 (SEQ ID NO:10), and GI#13279338 (SEQ ID NO:14)share 34% and 37% amino acid identity, respectively, with theDrosophila. CG6805.

[0117] Various domains, signals, and functional subunits in proteinswere analyzed using the PSORT (Nakai K., and Horton P., Trends BiochemSci, 1999, 24:34-6; Kenta Nakai, Protein sorting signals and predictionof subcellular localization, Adv. Protein Chem. 54, 277-344 (2000)),PFAM (Bateman A., et al., Nucleic Acids Res, 1999, 27:260-2;http://pfam.wustl.edu), SMART (Ponting CP, et al., SMART: identificationand annotation of domains from signaling and extracellular proteinsequences. Nucleic Acids Res. 1999 Jan 1;27(1):229-32), TM-HMM (Erik L.L. Sonnhammer, Gunnar von Heijne, and Anders Krogh: A hidden Markovmodel for predicting transmembrane helices in protein sequences. InProc. of Sixth Int. Conf. on Intelligent Systems for Molecular Biology,p 175-182 Ed J. Glasgow, T. Littlejohn, F. Major, R. Lathrop, D.Sankoff, and C. Sensen Menlo Park, Calif.: AAAI Press, 1998), and clust(Remm M, and Sonnhammer E. Classification of transmembrane proteinfamilies in the Caenorhabditis elegans genome and identification ofhuman orthologs. Genome Res. 2000 Nov; 10(11): 1679-89) programs. Forexample, the Inositol polyphosphate phosphatase family, catalytic (IPPC)domain of PIB from GI# 4314432 (SEQ ID NO:10) is located atapproximately amino acid residues 433-512 and 545-786 (PFAM00783).Likewise, the IPPC domain of PIB from GI# 13279338 (SEQ ID NO:14) islocated at approximately amino acid residues 12-326. Further, theEndonuclease/Exonuclease/phosphatase family (PFAM 03372) ofrepresentative PIB sequences of GI# 4314432 (SEQ ID NO:10) and GI#13279338 (SEQ ID NO:14) are located at approximately amino acid residues437 to 778, and 16-318, respectively.

[0118] II. High-Throughput In Vitro Fluorescence Polarization Assay

[0119] Fluorescently-labeled PIB peptide/substrate are added to eachwell of a 96-well microtiter plate, along with a test agent in a testbuffer (10 mM HEPES, 10 mM NaCl, 6 mM magnesium chloride, pH 7.6).Changes in fluorescence polarization, determined by using a FluoroliteFPM-2 Fluorescence Polarization Microtiter System (DynatechLaboratories, Inc), relative to control values indicates the testcompound is a candidate modifier of PIB activity.

[0120] III. High-Throughput In Vitro Binding Assay.

[0121]³³P-labeled PIB peptide is added in an assay buffer (100 mM KCI,20 mM HEPES pH 7.6, 1 mM MgCl₂, 1% glycerol, 0.5% NP-40, 50 mMbeta-mercaptoethanol, 1 mg/ml BSA, cocktail of protease inhibitors)along with a test agent to the wells of a Neutralite-avidin coated assayplate and incubated at 25° C. for 1 hour. Biotinylated substrate is thenadded to each well and incubated for 1 hour. Reactions are stopped bywashing with PBS, and counted in a scintillation counter. Test agentsthat cause a difference in activity relative to control without testagent are identified as candidate p53 modulating agents.

[0122] IV. Immunoprecipitations and Immunoblotting

[0123] For coprecipitation of transfected proteins, 3×10⁶ appropriaterecombinant cells containing the PIB proteins are plated on 10-cm dishesand transfected on the following day with expression constructs. Thetotal amount of DNA is kept constant in each transfection by addingempty vector. After 24 h, cells are collected, washed once withphosphate-buffered saline and lysed for 20 min on ice in 1 ml of lysisbuffer containing 50 mM Hepes, pH 7.9, 250 mM NaCl, 20 mM-glycerophosphate, 1 mM sodium orthovanadate, 5 mM p-nitrophenylphosphate, 2 mM dithiothreitol, protease inhibitors (complete, RocheMolecular Biochemicals), and 1% Nonidet P-40. Cellular debris is removedby centrifugation twice at 15,000× g for 15 min. The cell lysate isincubated with 25 μl of M2 beads (Sigma) for 2 h at 4° C. with gentlerocking.

[0124] After extensive washing with lysis buffer, proteins bound to thebeads are solubilized by boiling in SDS sample buffer, fractionated bySDS-polyacrylamide gel electrophoresis, transferred to polyvinylidenedifluoride membrane and blotted with the indicated antibodies. Thereactive bands are visualized with horseradish peroxidase coupled to theappropriate secondary antibodies and the enhanced chemiluminescence(ECL) Western blotting detection system (Amersham Pharmacia Biotech).

[0125] V. Expression Analysis

[0126] All cell lines used in the following experiments are NCI(National Cancer Institute) lines, and are available from ATCC (AmericanType Culture Collection, Manassas, Va. 20110-2209). Normal and tumortissues were obtained from Impath, UC Davis, Clontech, Stratagene, andAmbion.

[0127] TaqMan analysis was used to assess expression levels of thedisclosed genes in various samples.

[0128] RNA was extracted from each tissue sample using Qiagen (Valencia,Calif.) RNeasy kits, following manufacturer's protocols, to a finalconcentration of 50 ng/μl.

[0129] Single stranded cDNA was then synthesized by reverse transcribingthe RNA samples using random hexamers and 500 ng of total RNA perreaction, following protocol 4304965 of Applied Biosystems (Foster City,Calif., http://www.appliedbiosystems.com/).

[0130] Primers for expression analysis using TaqMan assay (AppliedBiosystems, Foster City, Calif.) were prepared according to the TaqManprotocols, and the following criteria:

[0131] a) primer pairs were designed to span introns to eliminategenomic contamination, and

[0132] b) each primer pair produced only one product.

[0133] Taqman reactions were carried out following manufacturer'sprotocols, in 25 μl total volume for 96-well plates and 10 μl totalvolume for 384-well plates, using 300 nM primer and 250 nM probe, andapproximately 25 ng of cDNA. The standard curve for result analysis wasprepared using a universal pool of human cDNA samples, which is amixture of cDNAs from a wide variety of tissues so that the chance thata target will be present in appreciable amounts is good. The raw datawere normalized using 18S rRNA (universally expressed in all tissues andcells).

[0134] For each expression analysis, tumor tissue samples were comparedwith matched normal tissues from the same patient. A gene was consideredoverexpressed in a tumor when the level of expression of the gene was 2fold or higher in the tumor compared with its matched normal sample. Incases where normal tissue was not available, a universal pool of cDNAsamples was used instead. In these cases, a gene was consideredoverexpressed in a tumor sample when the difference of expression levelsbetween a tumor sample and the average of all normal samples from thesame tissue type was greater than 2 times the standard deviation of allnormal samples (i.e., Tumor—average(all normal samples)>2×STDEV(allnormal samples)).

[0135] Results are shown in Table 1. Data presented in bold indicatethat greater than 50% of tested tumor samples of the tissue typeindicated in row 1 exhibited over expression of the gene listed incolumn 1, relative to normal samples. Underlined data indicates thatbetween 25% to 49% of tested tumor samples exhibited over expression. Amodulator identified by an assay described herein can be furthervalidated for therapeutic effect by administration to a tumor in whichthe gene is overexpressed. A decrease in tumor growth confirmstherapeutic utility of the modulator. Prior to treating a patient withthe modulator, the likelihood that the patient will respond to treatmentcan be diagnosed by obtaining a tumor sample from the patient, andassaying for expression of the gene targeted by the modulator. Theexpression data for the gene(s) can also be used as a diagnostic markerfor disease progression. The assay can be performed by expressionanalysis as described above, by antibody directed to the gene target, orby any other available detection method. TABLE 1 breast . . colon . .lung . . ovary GI#18593949 5 11 . 4 30 . 3 13 . 3 7 (SEQ ID NO: 2) SEQID NO: 7 0 12 . 2 30 . 0 14 . 2 7 GI#7209856 3 12 . 4 29 . 3 14 . 3 7(SEQ ID NO: 6)

[0136]

1 14 1 133893 DNA Homo sapiens 1 taacgcggat ttgcaatact taatgatcctgtaggaacac agagcctggc ggctgaagtt 60 gactgaccca gtatcttcaa tatattaccttcccagagct ggcctttggt ctacttggtc 120 tggcccacct cacaggaatt gagcaagaaagagaacacga gagttgaata tccctgcagg 180 aaccaccagg gaacttgatc tcatgaggaaatttctctgt agcattctta aattcaatta 240 tcaagttcta gagaactgta ggaattcatcatctgccttt tctgtccctt taactccaag 300 aatttctaga ccagggtgta gtgagacacctagaaatgtt aatcttagat atgaagacta 360 tgaatttggg tgataaataa caggcatgatcccagcagag gtctcatttc tgtgagcaca 420 tgcttattca cacagaagct ttctgccaggaaccctggca tgcctgagcc tgtctacgct 480 gctcattaga ctgctgctgg accacacgtaggcagaaatg ggacctgcat tccaagaatg 540 tctacatcac actcatagaa ggctggaatgggaagaactc tgaataagtt tattggaact 600 tggaaacaca taaaccagct ttgaaattttaaagtctaag tggtgtttag gttcctaggc 660 tagcccatgg agatttggcc ctcaaatacaggatcagaag aacagagaag gctgaaagga 720 ctggcttctt ttcattgggg ctgcactggtccttttctct ggttccctct aatcttccta 780 tctacttagt agataggaat gaatcttcaaagattcatta aagatcctat tatttgccag 840 gcattcaaga tacagaaata aaacttttttttcagtctaa agggagacac agacaagtga 900 accaacaagg caacccagtg tactgggaactgacagaagt gtgtacatag tacctgaaga 960 cagggaatgc tggggaggat gtagacacagtacaaggaac aagtgcataa ttcatggtaa 1020 ggcagcaagg gctgggacta agggaagaagaaaagccttt gactctcagt gcccttcagc 1080 cctggcctgc ctggctcaca taccctatagggtacctaac ccagatctgc ctaaccttcc 1140 aaagggctcc atgattttaa cgtctctttttctccccaac tagctcccat tacctggtta 1200 aataaactgg tacgtccaca taatagattacacagccact aaaaataatg cttccacaga 1260 gattttgctt acgtaggaat ttcaattacatgacataatg ttaagtgaaa aaaacaggat 1320 gggctggaca cggtggctca cgcctgcaatctcagcagtt tgggaggctg aggcaggcgg 1380 atcacgaggt caggagatcg agaccatcctggctaacacg gtgaaacccc gtctctacta 1440 aaaatacaaa aaattagccg ggcatggtggcgggcacctg tagtcccagc aactcgggag 1500 gctgaggcag gagaatggtg tgaacctgggaggcggagct tacagtgagc tgagatcgca 1560 ccactacact ccagcctggg tgacagagcaagactctgtc taaaaaaaaa aaaaaaagaa 1620 aaagaaaaaa gcaggatgta aaattgtatacaaagttgaa tatatatgtg gccaggtgcg 1680 gtgggtcata cctgcattcc tagcactttgggaggctgag gcaggaagat tgcttgagcc 1740 caggatttgg agcagctggg agtctgacacaggagaattg cttgaacctg ggagggagag 1800 gctgcagcga gcccactgca ctccagcctgggcgacagag cgagattctg tctcaaaaaa 1860 aaaaaaaatt gaatttattt gttatcagcaggttaaaaag ataccaaaaa aagaggtcaa 1920 aaatattaac tgtagtagtc tccggacagtggacttatgg acaaatttct taagctttaa 1980 aaaatactta catgtacttg ccaccttttccatagtgagt actctgttaa tactcaggag 2040 aaaataggcc aagcatggtg gctcacatctgtaatcctag cactttggga ggccaagatg 2100 ggaggattgg ttgaggccag gagttcgagaccagcctggt caacacagag agctcccatc 2160 tcaaattaca aaataaaaga tgtgaaaggtccaatacctt cagatctcag tagagaacaa 2220 aaaggaaacc aatctgaatt aagtacattcacaactgagg tgtgaatggt ccttagaata 2280 ataatcatct cagaaatttt aacaattttaattttatgaa tttatttttt taataagtaa 2340 cacgtttaca tggctcaaaa ttcaataggtacaacaaaag gatataggct gaaaagtctc 2400 tccctatccc tggaacccaa cagccctgttttctaccttc aagactgctt gactatatta 2460 ttagtataaa ccctagaagt agaactgcagggtcaaagta tttatatttg taactttgag 2520 acagtgctga atacccccag ggaagatgtgccaatttata ttcctatgag aaatacataa 2580 gacatttgtt tccctaagtc cttgacaatgacatgtatgt tttccaaaag atgatatatg 2640 gctttttttt ttttttgaga cagtttcactcttgttgccc aggatggagt gcaatggcgt 2700 gatctcggct cactgcaacc tccacctaccgggttcaagc aattctcctg catcagcctc 2760 ctgagtagct gggattacag ctgtgcgccaccacatccag ctagtttttt gtttgtttgt 2820 ttgtagagat ggggtttcgc catgctgcccaggctggtct tgaactcctg ggctcaagca 2880 atccacctgc ctcagccttg gcctcccaaattgctgagat tacaggcaat cagccaccaa 2940 gcccagagat aacacatatc tgagtggggattctagagcc agctgttcct actttttcac 3000 attttcgtcc actacttttt ttttttttttttaatttgag acggaggctc gctctgtcgc 3060 ccaactgaag tgcaacggcg cgatctcggctcaccgcaac ctctgcctcc tgggttcaag 3120 cgatcctccc atctcagcct cccaagtagctaggattaca ggcacccgcc accacaccca 3180 actaattttt ttggtatttt tcgtagaggccgagtttcag catgttggtc aagctggtct 3240 cgaactcctg acctcaggtg atccgcccacctcggcctcc caaagtgctg ggattacagg 3300 catgagccac cacacccagc ctcttccattatttttaaat acaaagaatg ttttgttcat 3360 ttgttgggtt ttaagcttca attatttttgaaaaattacc atgtttcatt tttaaaaaag 3420 gacaaaatgg aggacaagaa tggtggctcactcctgtaat cttagcactt tgggaggccg 3480 aggcaggagg atcagttaag gccaagagttcaaaactagc ctgaacaata tagtgagact 3540 ccatcaccaa aaaaatttaa aattagccaggtatggtggc gtgtgcctgt agttctagct 3600 ccttgggagg ctgaggcagg atgctcacttgagcccagga gctcaaggct gcagtgagcg 3660 atgatgacgc cactgcactc caacctaggagacagaagga gactctgttt cttaaattaa 3720 aaaaaaaaat tttttttaaa gagtgaaatgggatttgtac taccactggc acaaactttt 3780 aagtgtcatc taagaagttg ccttttgtcataaaatgttc cttaactttt ttccttaaaa 3840 actagcacgg cacagaggaa tgtgatggctgagttcaaat ctcagctctg caacttattc 3900 tgtgatttca gacaagttat tttctttctgagcctttgtt tttctcattt gctaaaatga 3960 ggctaatatc ttcctcacaa gacagttctaagaaatagag ataaaacagt acgggactag 4020 catagtgcct ggcacatagt taagtactcatgaaatgtta atccccctcc cttttaaggt 4080 ctctgagttc actgaaggta aactgtttttgtatattcct catagacata tgcaaccagc 4140 aggtacttgg ttaatttgct gagtaaatgagtcacaactt tcctttctca atgagcatca 4200 ttccttgaat gcagagtaga tgagacatcagaactgtgta tgtttatgaa ctgagaggaa 4260 atctaaaatt agatacaatt tgacccagagaaaatcagat tttccccaag tgttaaaatt 4320 aggggacact tgttatattt cttatcactataagtaacat agctaacact gctcagccct 4380 ctacatgaat tatctcattt aatctttatggcctgccttt aggtaaacac tactgtatca 4440 tcattagcat cccttgggat gttaaataaaggctcagagt agttaggtca cttgcccatg 4500 gtcacagacc tagtcagagg caaagcttcccaacccaagc caacgtcctt aacaaatggt 4560 aactcagtga tctgttcttg tgcgtcttgtcaagcgcaga cccagcttcc aggttcctta 4620 ctcagcacag ggctaggtgc ctcaggagcacctgatatat acatacgtgt gtgtgtgtgt 4680 gtgtgtgtgt gtctgtgtgt gtgtgaatgagttgacagat ctgatgccca ggagcaatta 4740 gaactgtaca actcaatata gccaactagagttgtggaaa atcagtatcc tataacagca 4800 aaacatgctg ttcagaactg gaaatgttacataacttaga gtcaattttt ttttttttaa 4860 gtattaccca aaactcttac acaaatgaaaaaaaaattga gggatctgca accagaagta 4920 gtttcaagtt ttctcaaatt tctccctattaaagataaca tactcacaca gaggtttggt 4980 tatccactga actattaccc actccagtgagatacctcct agggccaaca gcacagttcc 5040 tgacaggaag tagatgtttg attaaggtatgtgaatgaat gaaggggatt taatttcaat 5100 caaaccaata cagctgagga aaatagtgttttaaagaaaa gctcttcaga ctggacagat 5160 accagtcaag ggctgtgaat ttctagtataacaccatgaa agaaataatc tggagccaga 5220 ggacttagcc taaggctcag gtctgtcactcactatgcca gtgtccttac ctgcaaatgg 5280 ggaataattg ttccagccat ccctttgtcatgagaaaagt ttaaaaaata agggttttgc 5340 tttttttttt tttttttttt gagacggggtctcactctgt tgctcaggct ggagtgtagt 5400 ggcaagatct tggctcactg caacctctgcttcctgggtt caagtgattc tcctgcctca 5460 gcctcctgag tagcggggac cacaggtgtgcaccatcatg actggccaat ttttgtattt 5520 ttagtagaga tggagtttca ccttgttggccaggctggtc ttgaactcct gacctcaggt 5580 gatgcgcctg cctcggcctc ccaaagtgctgggattacag gcatgagcca ccgcgcccag 5640 ccttgttgtt attttaaata agtatgaaacagtgcctagc ccctattaga caaagaaatt 5700 aatgaggaag cagtaagatt aatattctgaattcatgatt gcaggtgtgc accacaatgc 5760 ctgcctaatt tatttgtatt ttcagtagagacagggtttc gccatgttgg tcaggctggt 5820 ctcgaactcc tgacctcaag tgatctgcccgcctcagcct cccaaaatgc tgggattaca 5880 ggcattagcc accacacctg gccaggtttcacttttattt tcacacagtc agtgaaatct 5940 cattaattca tattctataa aatgtcattaattcatattt tacctgaggt tgagctaaag 6000 acctctaaga tattctgaag gtagagtataaaaacaataa gtttgacaag atctaaccaa 6060 ttaagtagaa aactttttaa attttaatacccggtatata cttgacaaaa caatgatctc 6120 acttctcctt tctttttttt gagatggagtttcgttcttg ttgcccaggc tggagtgcaa 6180 tggcgcaatc ttggctcacc gcaacctccgcctcctaggt tcaagcgatt ctcctgcctc 6240 agcctcctga gtagctggga ttacaggcatgcaccaccac acctggctaa ttttgtattt 6300 ttagtagaga tggtgtttct ccatgttggtcaggctggtc tcaaactccc gacctcaggt 6360 gatccgcttg cctcggcctc ccaaagtgctgggattacag gcacaagcca ccatgcccag 6420 cctctcactt ctttcaacag aaggtcctgactaggaccaa ctgtgattaa agataaaacc 6480 aaaatgatac cattttgaaa agtctataatattgactttt acaaattgct cttgtgcctt 6540 gagccacctc cattgtattt gttaccagtgctgtttggca aacacttaga gaatgccaac 6600 taccagaccc atgataaaaa taaatcagggctgggtgcag tagctcacgc ctgtaatccc 6660 agcactttgg gaggccaagg cgggtggatcgcctgaggtc aggagttcaa gaccagcctg 6720 gccaacatag tgaaaccctg tctctactaaaaacaccaaa aaaaaaaaaa aattagctgg 6780 tcatagtggt gggcgcctgt aatcccagctactagggagg ctgaggcggg agaatcactt 6840 gacccaagga ggcggaggtt gcagtgagccaagatggcgc cattgcactc cagcctgggc 6900 aacaaaactc tgtctcaaaa ataaataaataaataaataa ataaataaat aagtaaatca 6960 gagaaggtcc tggttcctgt gctcaaggagtttataacca agtcagaatg taactattaa 7020 aaaacaaaaa gcttctcaca ctaagaagtgccttggcaga gatgatagtg ttaagaaaaa 7080 acaacaaact tccttaggct ttgcccaggatccactcctg tattcagaga cctgtccatc 7140 tttaaaaacc cccacatgcc aggcacagtggaacatgcca gctactcagg aggctgaggc 7200 aggaggattg cttgaggaca agagtttgagaccagcctgg gcagcataca aagaccttgt 7260 ctcaaaaata aataaataaa tattaaaaaataaaaacctg gccaggcgtg gtggctcaca 7320 cctgtaatcc cagcactttg ggagtacaaggtgggtggat catctgaggt caggagttcg 7380 agaccacctt agccaacatg gtgaaaccctatctctacta aaaaatacaa attagctggg 7440 tgtggtggca catgtctgta atcccagttacttggaaggc tgagacatgg gaatcgcttg 7500 aaccctggag gtggaggttg cagtgagctgagatcatact accgcactcc accctgggtg 7560 acagagtgag actctgtctc aataaataaataaaataaat aaaaaataaa aaccacatct 7620 ggccagaggt ggtggctcat gcctgtaatcccagcacttt gggaggccaa ggcgggtgga 7680 tcacaaggta aggagatcga gaccatctggctaacatggt gaaacctcgt ctctactaaa 7740 aatacgaaaa aaattagcca ggcctggtggcaggcaaatg tagtcccagc tactcggggg 7800 gctgaggcag gagaatggca tgaacccgggaggcggagct tgcagtgagc agagattgca 7860 ccactgcact ccagcctggg cgactgaacaagactctgtc tcaaacaaac aaacaaaaaa 7920 aaaaaacaaa aaaccacatc actgttacatcacaaggcac ttctgaggag caattaagag 7980 agcgagtatc agagtcaggt gctatagaaactatcacagg aattaacctg gcaactggac 8040 ccaggacaga atggccagtg agtcccctaggccatttcca cagaagcaga cacaatctgg 8100 ctcaatgaac atagaagtgc tgcttctaatctttgcatgt ccttaggcca gctggaagac 8160 aaggatccaa cactcgggag ctttgttcccaacgaccaat gaaatgaaga gatggactcc 8220 tgtcatctac agcagatgca gagtagagaagtacggtttg aaggctgggt gtggtggctc 8280 agccagtaat cccagcactt tggaaggtggaggcaggcag atcacttgag cccagaagtt 8340 tgagaccagc ctgggtaaca tggcaaaaccccatctctac aaaaaaatac aaaaattagc 8400 caagagcagt ggcgcatgcc tgtggtcccaactactcaag aggcaaaggt gggaggactg 8460 cttgagtccg ggaggcagag gttgcagtgagctgagatca cgccactgca ctccagcctc 8520 ggcgacagag agaccctgtc tttaaaaaactaaaaattaa aaaaagagaa gtagggtatg 8580 ataaccaggc agcaattagg gccgcctctgagaattttaa accaggagcc acttggtcat 8640 gactttaaaa actatatttc tggcaatgatttcttggaat gacaccaaaa gtacaggtaa 8700 caaaagaaaa agtagacaaa ttggatttcataaaaattta aaaattttgt gcataaaaag 8760 acactaccaa tagagtaaaa tggcaattcacagaatggga gaaaatattt gcaaatcata 8820 tatctgaaaa ggaattaata tcctgaatacatagataact cctaaaactt aacaacaaac 8880 aacctgattc aaaagtgggg ccaggtatggtggctcaggc ctgtaattcc agcactttgg 8940 gaggcttagg caggcagatc acttgaggtcagaagtttga gaccaacttg ggcaacatgg 9000 tgaaaccttg tctctactaa aaatacaaaacaaattagcc aggtgtggtg gcacacgcct 9060 gtacttccag ctacgtgcga ggctgaggcaagataattgc ttgaacccag gaggtggagg 9120 ttgcagagcc cagattccac cactgcactccagcctgggc aagagagaga gagactctgt 9180 ctcaaaaaaa atttttaaag ggtggtggtggggcgggggg gcaaaggact tgaatagaga 9240 catttcttca aagaagaaat acaaatgtcccaaaagtaca cagaagggtg ctcaacatca 9300 ctaatcatca gggaaatgca aatcaaaagcacaatgagat accatcagaa tgactactat 9360 ttttataaca ccagaaaata acaagttttggcaaggatgt agagaaatag aacccctgtg 9420 ctctgttggt gggaatgtaa aatggtacagctgctgtgga aaacagcaca gaggctcctc 9480 aaaaaaatta aaaactgaac taccatatgatccagcaatt ctacctctag gtatgtaccc 9540 aaataattga aagcaaggtc gcaaagaaatagctatacat caatgttcac agtagcagta 9600 ttcacaatag ctgaaacatg gaagcaatccaagtttgcat cgacagatga atggataagc 9660 aaaatacata caacggaaaa tcattttatcttaaaaagga agaaaaattc tcacatatgc 9720 tacaacataa atgaacctca agaacatcatgttaggtgaa gtaagtcagt caaaggaaga 9780 caaatactaa gctgggtgca gtggtgcccacacataaccc cagctacttg ggaggctgag 9840 gcagaaagtt cacttaaacc caagagtctgacaccagcca cacggttagg cctcatcttc 9900 aaaaataaaa aggacaaata ctgtatgattctacttatat gacgtactta gagtaaacaa 9960 aatcatagag acagaaagtg gaatagtggttggcagtggc tagggggaag aagaaatagg 10020 gagttattgt ttaatagaca cagagtttcacttttgcaag atgaaaacag ttctggaggt 10080 agatggtggt gatgtttcta gaacatgaatgtacttaata ccactgagct gtacatttaa 10140 aaaaatggtt acgatggtaa attttatatgaatttcacta caatttaaaa aactgggccc 10200 aggtacggtg gctcatgcct ataatcccagcactctggga agccaaggca ggcggatcac 10260 ttgaggtcag gcgttcgaga ccagcctgggcaaatggcaa aaccccatct ctactaaaaa 10320 tacaaaaatg agccaggtgt ggtggtgagcgcctgtaatt ccagctattt gggaggctga 10380 agcacaataa ttgcttgaac ccaggatgcggaggttgaag tgagctgaga tgacaccact 10440 gcactcagcc tgggtgacaa cggagtgagactgtctcaaa aaaaaaaaaa aaaaaaaagg 10500 aaaaaacccc cctacgtttc cataaaaggtcatacattgt gtgattttct tattagaatc 10560 ttattagaaa tatccagaat aggcaaattcatacagatag aaagtggatc agaggttacc 10620 aggagctggg gggaggagag aatgaggagttattgcttca tgggtagagt ttctgtttgg 10680 tatgctgaaa aagttttaga aatagtggtgatggttatac aacattgtga atttacttaa 10740 tgccactgaa ttgtacattt aaaaataattaaaatgggcc aggcacaatg gctcactgct 10800 gtaattccag cactttaggg ggctgaggcaagaggattgc ttgagcctca gaggttgagg 10860 ctgcagtgag ttgccactac acttcagcctaggccacaga gtgagaccct atctcaaaaa 10920 aaatttaaat agataaaatt agttaaaacagtaaatattg ttatgtacat cttaccacaa 10980 taaaaaaaat tttaagaaaa tctatgctccttatttaaaa atcaaaacta catttctatc 11040 ccactaagaa cacaccaagt acttattatacacattacgt ctacatagta agacttatta 11100 aataaatgaa cagttaagga aatggaaatctatgtaggcc atcagaagta acgcttatag 11160 gccaggtgtg gtggctcacg cctgtaatcccaacactttg ggaggctgag gtgggtggat 11220 cgtctgaggt caggagttcg agaccagcctggccagcatg gtgaaatccc gtttctacca 11280 aaaatacaaa aattagctgg gcatggtggcaggcacctat aatcccagct actcgggagg 11340 ctgaggcagg agaatcattt gaacccgggaggtggaggtt gcagtgagcc aagatcgcac 11400 cattgcactc cagcctgggc aacagagccagactctgtct cgagaagaag aagaggaaga 11460 ggaagaggaa gaagaagaag aagaaggaggaggaggagga ggggaaggga aggggaaggg 11520 gaaggggaag aagaagaaga agaagaagaaatgcttatag aagaggctgg caaaaacatg 11580 gagacattaa aattaaagtg tgtgttttcttcagttttag atgttaataa gaaaaagcaa 11640 gatatggacc tgtgtacagt gagtgattccaactattaaa aatgtgcccc gtagcaggaa 11700 acaagaagga aatatagcaa ctgcaacaaaggttctctag atactagagc tagggatgac 11760 tagggtgggg agagggagat ttttctgtatttcccaaaat gtctaaaatg agcacatcgg 11820 cagggcatgg tggctcatgc ctgtaatcccagcactttgg gaggctgagg tgggcggatc 11880 acttgaggtc aggagttcga gaccagcctggccaagatca tgaaacccca tctctactaa 11940 aaatacaaaa attagtcggg catggtggcacttgcctgta attctagcta ctcaggaact 12000 gaggcacgag aattgcttga atctgggagatggaggctgc agtgagtcaa cactgtgcca 12060 ctgcactcca gcctgggcaa cagagcaagactccatctct aaaaaaaaat aataataaaa 12120 taagcacata ctactttcac aatttacattactgaagctt ttgtttgttt caaggtatgt 12180 gtccaagatg gtttggttat ggccaaatgctgtagggtca agataggcct aggagcactg 12240 tagttatgta gctatgagca gctagtcctgagcattcaaa ccaccactga ctcctctact 12300 ccctgcctat aaccagacat acagcagagtggcacccaaa atgaaggctc cctgactagt 12360 cttatcatat cttggatgac aacctcatttctggacgcaa atagtaccct tcctttcact 12420 tgcccatggc cactccaact ccacatggccagaagtggct gggtttgagt caagctctgc 12480 atggtcagta gcctcaaatg gaaatttactttgtgcttta gtatgtccaa atccaactac 12540 attcagatca gggacatact ggcattgcctcagaatttgc aggtcaaatc actgagttat 12600 ttcaagagat ctgcaaactc tttgaatacctacattcaaa attgtacacg ataacaaata 12660 actcaattac aaaatgagca aaagatctaaacagacattt ctccaaataa gatatgcaga 12720 tggccaataa gaacatcatc atcatcatcatcagccatta aggaaatgca aatcaaaacc 12780 acaatgagat atcacttcac acccactaggagagatataa tttttttagt gggcaataac 12840 aagtgttgtg gatgcggaga aactggaaccctcataaatt ttagtgcaaa tggccaggcg 12900 cagtggctca cacctgtaat cccagcactttgggaggctg aggcagacag atcacctgag 12960 gccgggagtt ccagaccagc ttgaccaacatagagcaacc ctgtctctac taaaaaaaaa 13020 aaaatacaaa attagccggg cgtggtggtgcatgcctgta atcctagctc ctcgggaggc 13080 tgaggtagga gaatcgcttg aacctgggaggcagatgttg cggtgagcca agattgcgcc 13140 actgcactcc agcctgggca ataagagtgaaattccatct caaaaacaaa caattaaaaa 13200 aaaaataaat tttagtgcaa atgcaggccgggtgtggtgg cacacctgta atcccagaac 13260 tttgggaggc cgaggcaggt ggatcacctgaggttgggac ttcaagacca gcctgcccaa 13320 catggtgaaa ccccactcta ctaaaaatacaaaaaacagc tgggcatggt ggcacacgcc 13380 tgtaattgca gctattcagg aggctgaggcaggagaatcg cttgaacccg ggaggggggt 13440 tgcagttagc tgagatcatg ccactgtattccagcctggg tgacagggtg agactccgtc 13500 tcaaaaaaaa aaaaaaaaaa aaaaagacaatgaggaactg tcccagatat ctgatgagac 13560 cagggagact tgacaactaa atgtgatgtaggatccagga ttgggtcctg gaacagaaaa 13620 aggacacagt gggacaaata gcaaaatctgaataaagtct ctagattagc tagtaatatt 13680 gtattaatgt taaatttctt gtttggataattctgatata attatgtaca gttttgacat 13740 taggtgaagt tagatgacag atatacagaaagtttgtgaa ttatttttgc aagtttagta 13800 taagagtaaa attatttcaa aataaaaaggccaggcgcag tggctcacgg ctgtaatccc 13860 agcactttgg gatgccaagg cgggtggatcacctgaggtc aggagttcag gaccagcctg 13920 gccaacacgg tgaaacccac ctctactaaaaatacaaaaa ttggccaggt gtggtggcac 13980 atgcctgtaa tcccagctac ttgggaggctggggcaggag aatcgcttga acctgggagg 14040 cacaggttgc agtgagctga gactgtcccaccgcattcca gcctgggcaa caagagtgaa 14100 actccatcta aaaaataata ataataataataaggggcca ggcacggtgg ctcaagcctg 14160 taatcccagc actttgggaa gctgaggtgggtggatcact tgaggtcagg agattgagac 14220 catcctggcc aacatggtga aaccccgtctccactaaaaa tacaaaaatt agccaggcaa 14280 ggtggcgtgc acctgtagtc ccagctactcagaaggctga ggcaggagaa ttgcttgagc 14340 ccgggaggtg gaggttacag tgagccgagattgcgccact gcactccagc ctggaggaca 14400 gagtgagact ccgtttcaaa taaataaataaataaataaa taaataaata aaataaaata 14460 aaaagttaaa aaacaataca tggctgggagtggtggctca tacctgtaat cctagcactt 14520 tgagaggctg aggcaggaga atcatttgagctcggagatt tgagaccagc ctgggcaaca 14580 tagtgagacc tcatctctac aagaaacctaaaagttagct gggtgtggtg gtgtgtgccc 14640 gtagtcccaa ctactcgggt ggctgaggtgggaagatggc ttcagcccag gaggtcaagg 14700 ctgtagtagg ctatgttcgt gccactgcactccagcctgg gcaacagagc gagtcactgt 14760 ctcaaaaaaa aaaaatgtac acgatgcaggtcaggaattg gcaatttttt ttccataaag 14820 ggccatagag taaatacttc agactctgtggaccatatgg tttttatggg aagtaatcaa 14880 ctccactgag tagcattaaa gcacccaaagacaatatgta aatatatatg aatataaata 14940 aatgggtgtg actgaaatga acactgaaattttatcttcc tgtaattgtc acctatgtaa 15000 tattattctt cttttatttc ccatcatttaaaaatgtaaa aagcaggcca gacgtggtgg 15060 ctcacgcctg taatcccagc accttgggaggctgaggcgg gcagatcacg aggtcaggag 15120 atcaagacca tcctggctaa cacagtgaaaccctacctct actaaaaata caaaaaatta 15180 gccagtcatc ggggtgggcg cctgtagtcccagctattcg ggaggctgag gcaggagaat 15240 ggcatgaacc caggaggcgg agcttgcagtgagctgagat ggagccactg cattccagcc 15300 tgggcaacag agcgagactc cgtcttaaaaaaaaaaaaaa aagaaagaaa aatgtaaaaa 15360 gcacccttag ctcacagacc atataaacaagcagtaggtc caggtttggt tcacagccta 15420 tatatagtat gcagatcccc actctaggtcagaatttgct aacgtgtgct tcaattaaaa 15480 aaaaaaaaaa gatttgacat caagtagattaaacaaatgg aacaagttat tatcttggct 15540 tataaggcac atttccttat tgcaggacctctcagtggtt ttaatgtggt attacacatt 15600 gagaagctcc aagaaagaat aatggtatgtggctttctca aacttattat tagcatcaaa 15660 tccttttttc agagccactt cttcagaccagtggcctgaa gaacatactt atgagaatgt 15720 caattcagac acttctttaa aaggaaacttttagatcgag aagttctaaa aactccaaca 15780 aattaagatc attttaccca gtacctggataacatctgaa taagcatttc acaacttttt 15840 tattttttaa tcttgggaaa cacaagtcgataactggcag gaagttttgg ctcaacccta 15900 acttttgtgg cggcggggga gcaagtcagcagaactgggt cataatatgg agcctctgct 15960 ccctaagaca acataaacat tcctaagcattctagcaggt gttgaaaaag tgatttaggc 16020 agagctttgt aatgcacaaa ataaggacataataatgttt gattagaaaa ccaaaggtat 16080 gctagaggcc aggcacagtg gcttacacctgaaatcccag cactttggga ggctgaggca 16140 ggcggatcac ttgaggtcag gagttcgagaccagcctggc caacatggtg aaaccccatc 16200 tctactaaat actcaaaaaa aaaaaaaaaaaagctggaac ttgtcatgtg tgtgaactgg 16260 caagtcaagt ctataagagg actgtttttatatgatgcat ggaaagctag ccaacagact 16320 gcaaaaattc tctcacatct atacacatattgctgaagag aggattcaag cagggattat 16380 gttccaggga agagaaggct ggtctgaacaacctcaaggg gtgctttcaa ctgagagtcc 16440 tcaattttgt gattcagagt tcactggcttctcctggtca aacataaaat cttcagaggc 16500 atttccaact tgttcttaga aaaaagctactaacccatgg ggtgggaccc agtttactta 16560 ttcattcaat aaacatttaa ggtgcctctatcagatattg ggtcattcca aagtccttga 16620 aaagaaggat ggtgcacagg acaaccaggaagagattatg taaggtcaga tgcattggcc 16680 ttatttacag gagatgtagg ctaaagtgatggaagtgtca aaagagaaga aaaaagtcac 16740 atttgccttg agagcagagt cagcaccagaaagatgcaga acaactcctt ggaatcacag 16800 actttcaagt tggaaaggac cttcatctaatacctatata cctccctcga aaggaggcac 16860 ggaggcaatc cattcactcc atcggtggtcacctctgacg attcttccat ttaagttctt 16920 ctattaagca aaaatcttgc cttcctgtagaattcacctg ttagtcctag ttctgcctct 16980 tttagcctaa agatgaagtg gaagccctctttgccgtaac agtattttca atttttaaaa 17040 agttaattcc cttccagtgc tctctttactgagctaacca ttccagttct ttcaaagttc 17100 ctgaactggc accagctgcc tcaaagcgaagaatggatat ctagtgctca cagcaggaaa 17160 gcacttaaaa tcaatgagct tcaaacattagtatatacag gaccccccta cgcataagtt 17220 cagattctaa accagaagtc tgaattgagtcccgcgctgt aaagccggca tctcagagaa 17280 ttacaaagca gatggtgtaa gaaccatattttgaaaaaca ctgccccgtt ttagagacga 17340 gaaaactgag gcccagcaca gggaagagatttggcccaga acgcacaatt gtctgtcggt 17400 ggcgaagtct cgaatccagg tctcttactttcagcccaac tctgttcacc gcgctccccg 17460 gcctctgctt ctccactcag ggcaaactcgtgaaatgcac tcccagatga tagaggcggt 17520 ctcgcacggg ggatagaatg ggaatcagtgcccatgcctc gaaaggagag cttgtgggag 17580 cccttctctt tcgcaaggcc tcagtttccccaatctgtat tcatgggacg cagaaccaca 17640 acgccagctc gtcctctttt cggggacagacacgaccggt cttgctgtct ctgggcccct 17700 gggctcagat gttcaagccc gtgtgtcctgggaaggcgga cccgggtctc ccgcccccgt 17760 ccctaaactt tggcgccccc gccccaaccccagcccctca catacctgcc tccgcacagt 17820 taacgccagc ccagtcaatc agtttttcgggtacacggcc aatactaacg ccgcgtcaat 17880 ctgttgggta agacctccga cccctcctacgcggactcca gtcacatgac gcggagccgc 17940 ccctctcgga gggacttccg gccccaaccggaagaggtta atttccatgg ctgaagctct 18000 aaggttccgc ctgcgggcag gaagcggaggaaccttggag cttcggcagc ttttcaaaga 18060 gctttgggtt cggggctcct aaaagaaaaaaactgattcc ggccgggcgc ggtggctccc 18120 acctgtaatt ccagcagttt gggaggccgcggcggatgga tcacttgagg tcaggagttc 18180 gagaccagcc tggccaaaat ggtgaaacccctctgtactc aaaatacaaa aagtagccgg 18240 tcgtggtggc gcacacctgt aatcccagctactcgggagg ctgaggcagg ataatcgctt 18300 gaacccggga ggcggaggtt gcagtgagctgagatcgcac cactgcactc tagcctgggc 18360 gtcagagtga gactccgtca aaaaaaaaaaaaaaaaagag agagagaaag aactaactca 18420 ttccggaaag taccagataa acttggaacatcttgttaca ccagaatata aggatgatgg 18480 taataagaat catgggaatg tgtcaaagaacacaggagct gtctttaagg agatcttact 18540 ggccaagtca gggcaatttc agaatcaaaatatggagtga tagtaataga gtataactaa 18600 ttgaataaaa tagtaatcca tgagtctttacaaacataaa gaagtgagca tattaatggg 18660 tgaagggaaa gtcttccttt tagtagaatgctagctaata aacatggtgg aattaggaaa 18720 tcaataatgt gtggtaaaac tagagaaacgggatgtttac aacagcaaaa gtgtctccca 18780 taaattagct attgattaca aagggaaaatggtgatgtta cagaggttta acctagcaga 18840 acaaacagat caaagtgatc aaagttaacaccactagtta atgggtcaga tcaagggcct 18900 cctaataaaa tgcactgaga acacatctgtggtatttctg tcaaaagtgc accgtacaca 18960 tctcatgagg aagtgctaga gaaccccaaatgaaggacac tgtctacaaa ataactcatt 19020 gtcatgaaaa acagagaaaa gctgaggaactgttccagtt taaaggagac taaagaagca 19080 tgacaacaaa atgtggtgtg tgattctaaataggaccctg gactggggta gtggtggtgg 19140 tggaatagtt gtaatggaca atattgggacaagtaatgaa atttgaatat ggattgtgga 19200 ttagctgtta atacatattg tatcaaatcacatactgata ggtgatggag cttgtgattt 19260 gcactcaagc agtcattgga gttcttgacagccatcttca ttcattcaac aagcatttat 19320 taagtaccta cagttatccc aggaacggttagggatcgga cctgagtagg aggtgaacat 19380 agtagataaa ggccggcgcg gtggctcacgcctataatac cagcactttg ggaggtcgag 19440 gcaggcagat cacctgaggt taggagttcgagaccagcct ggccaacatg gtgaaactca 19500 tctctactaa aaatacaaaa attagccaggcgtggtggcg ggcacctgta atcccggcta 19560 cttgggaggc tgaggctgga gaattgcctgaacccaggag acagaggtta tagtgagcca 19620 agatcgtgcc attgcactcc agcctgggcgacaagagtga aactccatct cagaaaaaaa 19680 aataaaaaat agtagatgaa ataagctcatagatgaaagt cctagtctgc cagccacctt 19740 tgcaagttcc tgtgatcaag aagtaatacaagggatgttt ccagtcacac aaacctggat 19800 ttgaaaccaa gcgctaagag aaaaacagcccctgacatcc aggagatggt ctggcactca 19860 caaatagacc ttggtgtgtt ctcttattgaacataaaaac ttcacagaac atcaacatca 19920 aacaaagcca ctatgtgacc atgatggatcaagacaataa caaaaccact tgaatcatgt 19980 ctaaacccag acaaaacatg agcattgttcgaactacaaa aatggccaaa catttcccta 20040 ttctggcttg tatagagatt atagatttagcctcggtcta ctcttccctc cttctaaata 20100 atgtttatca aggtactcac tcataggcagcatccaatcc agaaaacccc attttcttaa 20160 gccctcgtcc aaatcaccta atgcaagcccaaatcctatg tgtcctttgt aacactttgt 20220 tactgagatg cccctttgtt tgtttgtttgtttgtttgtt tgtttttgag acagagtatc 20280 actctatcac tcaggctgga gtgcagtggtgtgatctcgg ctcactgcag cctctgcctc 20340 ctgggttcaa gtgattcttc tgcctcagcctcccaagtag ctgggattac aggcgcccac 20400 catcactccc ggctaatttt tgtatttttagtagggacag ggtttcacca tgttggccag 20460 gctggtctcg aactcctgac ctaaggtgttcctcccacct tgggcttcta cagtgctggg 20520 attacagatg tgaaccacca agcccagctgccctattgtt tctcatgatt catgtcctct 20580 cacccttacc ccataacaag tgataaactcaacttgttta accacaggtg tgttccaatt 20640 tcttccttcc tcaaaaagtt gttatgaggatactcggaac aggttcatca cagagtgagc 20700 tttctctatc aatcgatcca ttatctattttttatttttt taaaaaaaca tggtctcagc 20760 ctgtggtcca gactggagtg cagtggcacaccatcctaac tcactgcagg cttcaactcc 20820 tgggctcaag tgatcctccc acctcagtctcctgaataac tgtgactaca ggcacgcacc 20880 acacccagct aatatttttt atttttctgtagagacaggg tcctgctgtt gcccaagctg 20940 gtctcaaact cctggcctca agggatcctcccagtttggt ctcccaaagt gttgggatta 21000 caggcatgag ccacctcacc caatgctttcaatatacttt taaaaattat acatatattt 21060 ttgagacagc acctcactct gtcactcagattggagtaca gtgatgccat cttgactcac 21120 ctcaacctcc gcctccctag ctcaagcgattctcctgtct cagcctcctg agtatctggg 21180 attacaggtg catgccacta ccacccagctaatttttgta tttttagtag agatgggatt 21240 tcaccatgtt ggccaggctg ctctcgaactcctgacttca ggtgatttgc cctcctcagc 21300 ctcccaaagt gttgggatta caggcgtgagccaccacgtt tccccctcag cttgcattgt 21360 ttctgggaga acctgcacca tacctttatctatagctttc ccccaggtct taagaagcac 21420 gaagttttaa ctgtggacac gggatttggtgaagcagcaa tcacgactgt gggcacgagt 21480 agcaaggctg cagcagcaca ttgactatagaatgaaatgc atcctacagg aaggcacaat 21540 cttctttggc atctttaagg cgtttgacaagcatgtgaat ttgatcctct gcgattgtga 21600 tgagttcaga aagatcaagc caaagaacgtgaagcaacca gagctcgaag aaaagcactt 21660 ttggggtctg gtgttgctgc atggggagaacttggtatcc atgactgtgg aggggctacc 21720 cccaaaatat actggcattg ctcgggtaccacttgctgga gctgcaggag gccctggagt 21780 tgttagggca gctggtagag gagtatcagctggtgtacca attccccagg ctcctggtgg 21840 attagcaggc cccgtcccag gagttgggggaccatcccag caggtaatga ctccacagag 21900 aagagcatta ctggagcccc aacacagtacccaccaggac cgggggctcc acccccacct 21960 gttggcagag cagccccacc tctaggcattatgtttcctc cacctggtat gaaaccaccc 22020 atgggcccac caattgggct tccccttgctagagggacgc cagtaggcat gccccctcca 22080 ggaatgagac cctttccacc aggaatgcatccaccaagac cctgggatat tgctgatcca 22140 tctcagtcac ttttccccct gcaatgcatcttgtgaaatt gtatagtgtt tgtgagcttt 22200 ttgtcccttc tttctgcgtt aatcatagctaataataaat gcctaaagca attaaactgt 22260 gggaaaaaag atattgaagc catcagctttcattaagata aactccctga ttatattcct 22320 ctttgctctt tttgttgggt tcataaggtggaaaaaatgg agagagttca acttttcctt 22380 agtcggaaat gaggtcattc tcatggtattttctggaaag caataaccac gttcctgaaa 22440 ctttaacatt agggaaccag cactgtttatttcttcatgt tcttgttatt aaaaacgttc 22500 ccaagaagta gcagaattgg aactaccaaacttggaagca cttcagcttc aaaaatatat 22560 caagtaatat cttctctgct ttagcacactaaggcactta taatccctgg aagccctgtt 22620 ggtgatgttg gcatttatcc tgctggaacccagcatagat ttaatattat ttgatgccta 22680 caacattgtg ctgaataaaa aatattcattccggtgggaa ataattttaa aaatataaat 22740 tttctgattt cttcctctgc ttgctcccaagtccccctgc cccctcccct tctttgccct 22800 tactccttta ataataataa tagcagtagctaacatttat tgaatgttta taaagtgctg 22860 catactgtgc taagggcttt atgcaatttaaccctcaccc caggattgtg aaggaagtct 22920 tactacagat gagaggctag aggaccagagaagttaagca acatgcccaa gactacacag 22980 ctggtaagaa tcaggcccaa aattggaatccgccctcaaa acctgctcct gttgaaatgt 23040 tgcttcacca ccctggcaca gagagtagggtctgtgaagg gatggaagga gtgatagact 23100 ggcaaggaag gaagggcttg gggtagtgggtggggtgggt gggagtggaa gaccatgcag 23160 aggcatttag accctctcca gagggcagagggaagggatg gagattagga acacaacaca 23220 aataggaggc ccctgtagaa cctcagggggagccatgagt ttgggggacc aggaaggttg 23280 aagagtgggt aaattaggcc aggcgcggtagctcatcatg cctgtaatcc cagcactttg 23340 ggaggctgag gcgggcggat gacctgaggtcaggagttcg agaccagctc agctaacatg 23400 gtgaaaccct gtctctacta caaatacaaaaattagctgg gcatggtggt gggtgcctgc 23460 aatcccagct acttgggagg ttgaggtaggagaatcattt gaactgggga ggcggaggtt 23520 gcagtgagcc gagatcacac cattgcactccagccggggc gacaagagtg aaattctgtc 23580 tcaaaaaaac aaaacaaaaa caaaaacaaaaaacaaaaaa caacaaccaa agagtgggta 23640 aattataagg tgggagaagg gcatgattaaggacctgggc cacaggtgtt tacttgccaa 23700 gtgaggagag gcaagaagtc tgggggaccttctggcccac ttgatttttt tttttttttt 23760 taacagagtc tccctctgtc acccaggctggagtgcggtg gcacaatctt ggctcattgc 23820 aacctctgcc tcctgggttc aagcgatttttcatgcctcg gcctcccgag tagctggaag 23880 caggcaggca ctcaccacta cacccggctaattttttgtc tttttagtag agacgggttt 23940 tcaccatgtt acccaggtgg tctcaaactcctgagctcag gcaatccgcc tgccttggcc 24000 tcccaaagtg ctagaattat aggcatcagccaggcctatt tgatcttcta ggactcacag 24060 gtccctgctc ttctctggga ctcaattttatgatctgttc aatgcaagga gagagagagg 24120 attccagcat cccagggagc accagctcttaaggaggtag catcactttc tcctccagtc 24180 tcctcacctg acatggggga gaaggttccctggacctagc catttcccta cccctacccc 24240 acattagtct ctcctcatgg gtacaggaggctgagagagg aagactgtgt ctgcagacag 24300 aagtgagaat aagccagaga aagcactccctgattctcct aaatcccagt tcttccacag 24360 aggagtgggc aggttaggag catggcctcattagtcccct gatctggggc aaataggcaa 24420 atctttgctg tgtgccctca gacaggccacccacccctgg gcctcaggct cctctcattc 24480 tctgtgtatg ggtgctaggg tcacgttgaagcctgctgct cccctgccat caagttccct 24540 gccccaggac agctcagggt ccgtctattcagtcttctac tggggcctgg cccagggctc 24600 tgcccttatg gtggccctgc tggtcaggggcagagtgaac cagcctgacc tttcagattc 24660 acgtctggta gtgatagtat tttttgtttagatacatagc caccaggtag tatctgagcc 24720 atattctgga atcttctgag agctaggtcagcaggactct attcttggga attaggccct 24780 ttccagagga ttctagtata ttcctagcaaagatgaagca tggccaaaag ttcaggaagc 24840 tggccaggca cagcggttca catctgtaatatcaacattt tgggaggccg acaagggagg 24900 attacttaag gctaagagtt caaaaccaggctgggcaata tagcaagacc ctgtctctac 24960 aaaaaaaaat ttagctgggc atggtggcattcatctgtag tcccagctac tgagaaggct 25020 gaggtgggaa gatggcttga gcccaggagcttcaggatgc agtgagctat gatcacgccg 25080 ctgcacttca gcctgggtga cagagtgagaccttttctct aaaaaaaaaa aaaaaagtct 25140 ggaaaccagg gaaagaaata ctagtgaagagaaggacaat acaaaaaggc actgagaaat 25200 tatggaatta tgggatcctg ggtagtgtggagagggaggg aggtggggca ctcattggac 25260 agtggagctg ccttgcacat ctgggagactgaaggaaggg cagatgtttg ctctgggcct 25320 actatgtgcc aggcattatg gggaggtccttccttttttc tttttttctt tttttctttt 25380 ttttttttga gacggggtct tactctgtcacccaggctgg aggagggcag tggtgcgatt 25440 ttggctcact gcagtctcaa cctcctcaggctcaggtgct cctcctacct cagcctcctg 25500 agtagctgga actgcaggca tgtgccacgatgcccagcta atttttgtat tttttgtaaa 25560 gacagggttt tgccatgttg tccaggctggtctggaactt ctggactcaa gcaacctgcc 25620 tgccttggcc tcccagatta ctgaggtcatagatgtgagc cactgtgcct ggccgggagg 25680 tccttttctt tttttctttt ttttttgagacagaatctca ctctgtcgcc caggctggag 25740 tgcagtggtg caatctctgc tcactacaacctctgcctcc cgagttcaag caattctcct 25800 gtctcagcat cctgagtagt tgggattacaggtgcgcgcc accacgccca gctaattatt 25860 ttgtattttt agtggaaacg gggtttcaccatgttggtca ggctggtctc aaactcctgg 25920 aggtcatttt ctcatacttt tctcagtgagtccttttaac agttcattga ggaaagaagt 25980 atttgtggcc actttacaga ggaggaagctgaagttcaga gaggtgagga aatgtgacca 26040 aggtcacaca acaaggaaat agagccagattcagtgcttc caagtccaga agggtgaact 26100 agaagtaggg ctgccagata aaatacaggatatgcccaat taaatttgaa gttcacataa 26160 acatcaaatt ttaaaaaata taaatatgtcccaaatatca cctgggacat acttacattt 26220 aaaaattatt atgctgggtg cggtggcttatgcctgtaat cccaacagtt tgggaagcca 26280 aggcaggagg atcgcttgaa gccaggaatttgagaccagc ttgggccaca tagaccccat 26340 ctctactaaa agttttaaaa attagccaggcgtggtggtg cacgcctata gtcccagtta 26400 ctcaggaggc agaaatggga ggatcacttgagcccaggaa ttcaaggctg cagtgagcca 26460 tgattgtgcc actgcactcc agtctgggcaacaaagcaag atcttgtctc aaaagaaaaa 26520 aaaattacat gttctttatc tgaaattcaaaattaacttg acttttcttt tttgctaaat 26580 ctttggtaga gggaatgcct acaccttgacggcataaaag ggcagagcct aggactgtgg 26640 ggtctgggag agaagtgaga gtgacttcgcgaccccttct caggcctcaa ggaggaggcc 26700 caggcactag caccaagcca ccagggtctacacaaaccag ggtctacaca gctcccggac 26760 aggtgtctag aaactttccc aggatgtagggcaatgaaca cttaaaggga caaaggccct 26820 cagactctcc ccaaccctgt accacatttattcaccctcc tccataccaa gaaattaccc 26880 tatcctttgt cctccatgtt cagaccaaaaacctgggaat cattcttgtt tccccaatgc 26940 tacatgtaga gctgtgctat ccgaaacagtggtcttcggt ctcatgtggc tgagtgcttg 27000 agatggaatc caaattgaaa tgcacaataagtgtaaataa aatacacaca ggatatcaaa 27060 aacttggtac caaaaaaggg tgtaaaatggcttgttaata atttaaaaat agtgattaca 27120 tattgaaata atattttaca catcggatcacataaagtgt attattaatc tttttttttg 27180 agaccgggtc tcactctctc atccagactggagtgcagtg gcaggattga tcaaagttca 27240 ttgcagcctg aagtcctgga ctcaaagtgatcctcccacc tcagccacca ggggtgcacc 27300 accaggtcca gctcacaaaa tgtcttattaaaattacttt cacctctttc ttttatgttc 27360 tcgatggcta gaaaatttca gattacatttgtggctagca ttggaattct gttgaccagt 27420 gtgggtgcag acatggtctg atttgttcatctgtaaaata ggtttggaga ggtggagtca 27480 ttggctcata gtcatacgca gcgtccaaccttggcatagt gggatgggaa atcaggttat 27540 tttgaaccct gagcccatgg ctacccgtcagccccctggg ctgacatttg acctcttcca 27600 gaatcatatg ccctcctgaa accacaaccagtcctcagtg gagacctaag gtatgctcgc 27660 ccatcctagt gtggggactt gggggtgggggtgggggcgg gggcttcctg aatgggattg 27720 taacccccca ccaaattcac cttgcctgctgcctagacag agccgattta tcaagacagg 27780 ggaattggaa tggggaaaga gtaattaatgtagagccggc tgtgggggag acccgagttt 27840 tattgttact caaatcagtc ttccagagcatttggagatc agagttttta aagataattt 27900 gtaggggctt aggaagtggg gagtgctgattggtcaggtt ggagatggaa ttataggggg 27960 tcgaagggag tttttcttgc tgtcttctgttcctgggtgg gatggcagag ctggttgagc 28020 cacattactt gtctgggtag tgtcagctgatccatccagt gcagggtctg caaaatacct 28080 caagcactga tcttagattt tacaatactgatgttatccc caggagcaat ttggggaggt 28140 tcagactctt ggagccggag gctgcatgaccctaaactgt aatttctaat cttgtagcta 28200 atctgttagt cttgcaaaaa cagactggtccccaccaggc aagaaaaggg tctttttgga 28260 aaagggctat taccaatttt gtttcagagtcaaatgatta actgaattcc ttcccaaagt 28320 tagtttggcc tacgcccagg aatgaacaaggtcagcttaa aggttagaag caagatggag 28380 tcggtgaggt ctgatttctt tcagtgtcatgatttcctca gttataattt ttgcaaaggt 28440 ggtttcagga tggctaagcc aacatctgaaggatgagtaa gaacaagcca ggtaaagaag 28500 ggggaaaagt gttttaggca aagggaacagcatgtgcaaa ggctcttaga gagtgtgtta 28560 attgagaata tgaatgtagt tccgtgtggttagaacagag atgtggggag taggtgaggt 28620 cagctgggct cagatcctgc agtgcccaccaggcttcagc atgagcctct ctggtcagaa 28680 gacagatgta gacagtggag agaactggctatgtttgtgt tttagaaaga ttgggcctgc 28740 taccgtttgg agaaccactg ttccaagagataaaattgag aaccagagaa gaaaagggct 28800 tgttcagggt catatagcga atcagagccaagaaggacta ggctagcagg cacaaccgac 28860 caggaaagga gcagacagcc ttgttcaggagtctcaagga ggcactggca tggggtgtcc 28920 actagatgac agcagaggct ggaccaaactccaggggctt cgggcaggac ccaccctgct 28980 tttccacaag ccttcctctt tccatttccctggtctgggc atcagagggc ctctttccta 29040 acccttttct ccagacccca gagcagcaaggagagccctg ggtgtcagga ggctcagaga 29100 ctagccctag ctccatttcc cctctgccattgacataggg caaattcaaa gattaaaaac 29160 tgcttgagaa cttgagtctt tggctgtagaaatagaagtg gcattattag tctaccagga 29220 gccacattct gtagttagat ctcctgctgagcctcttgat cctcctttaa tgctccctgt 29280 ccacccaccc tcttcattct atcttgtgagttagactccc agagactgtc aatggcccca 29340 aggcccaggc cagccctaag agggaaggaagggatgtgag ctaagttctc tgagttagag 29400 ccaacacaaa cagcccaggt ttaaacctcagccaaggggc cttgtgtaga acaaaatagt 29460 ggatatgtcg cagagctttg ggcaaatctgatctcctcct agggcctcca ttgtgaaatg 29520 aggtgaagag tccctgggtg tcttcacttcactcctgctg ggcagggtta ccagatatag 29580 taaacaaaaa cacaggatat gcagttaaattagaatttca gataactaaa aaagtaattg 29640 cagccaggca cagtggctca tgcctgtaatcccagcactt tgggaggcca aggcaggcag 29700 atcacttgag gtcaggagtt caagaccagcctggccaaca tggtgaaacc ctatctctac 29760 gaaaaataca aaaattagct gggtgtggtggcgggagcct gtaatccaag ctactcagga 29820 ggctgaggca agacaatcgc ttaaacccaggaggtggaga ttgcagtgag ccgagattgt 29880 gccactgcac tccagcctgg gtaacagagcaaactccatc taaaaaataa aaataaaaat 29940 aaataataat aattgcaatg tttgggcatatacttacata aaaattattt atcgttttct 30000 gaaattcaaa tgtaactaga cttttttttttttatctgac aactctagta ctgggacatg 30060 gtaggatgtc aagtggtgtt ggaacaggaggggagtgaat cttgcactca gcatcattct 30120 atcccatacc ccaaggtcct ttggggcttcattgtccagg taggtagatc tctcacagcc 30180 cattctgccc cttgtttcta ctggatttccctatagtttc tggcttactg tgaggcattc 30240 ccctcagtga gctccttccc caactctgatcttcactgca ctccagggaa gaaagaaaag 30300 taggcataag catcccaatc agtagagtgtataacaggga ttcagccaaa gtaactgact 30360 tgcccaaggc tgcccaggag gggaagtggagctaggggtt gaacccaggg tatagggaag 30420 gatctcctgg gcttcttaga accccactagcaggctggag tcatctgggg acatacaagg 30480 agcccacatt ctacagcctg gtgaactgaatatcaggtca gtcacaccac catcttgcct 30540 ggcttctgcc ctcaagtgcc ctccttaaatgaagatctca tttgtcaaag gctactgtgt 30600 gtcagtcact gaggcacttt agttacactcacattaatcc tcatggcata aatgttatta 30660 tctccgcttt accaatgagg cccaaagaggcaaaaagact tggctgagat cacacagaaa 30720 gtgagaaaaa gtctaggtct caaatttgggtctgatctgg gcttattcca tcctaccata 30780 ctgccttccc tacaccaatg gtgttagatacacctggagt ttttaggtgg aagactaatc 30840 tgcaaacaat aacagttttg tttcttcctttccaaacttg acaatttgta tttttttctt 30900 gtcttattgc attggctggg acttttagtagcattaatag taggtaccca tgatgtgttc 30960 ctgattttaa tagaatgttt ctatgttagttacctattgc tgtgttaaaa aaaattagca 31020 tctcaaacaa acatttatta actcacagtttctgaaggtt aggaattcaa gagtagctca 31080 gttgaatagt tctggctcag aatgcatgaggttacagtga tgacatcagc cacatttctc 31140 caaagaaaat acaggtcgag catccctaatccaaaaatac aaaatccaaa atgctccaaa 31200 atccaaaagt ttttgagtgc taacatgatgctcaaaagaa atgcttgttg gagcatttaa 31260 gattttgggt tttctgatta gagatgcccagctggttaag tataatgcaa atattccaaa 31320 atctgaaaaa aacccaaatc tgaacacttctggtcccaaa catttcagat aagggatact 31380 caacatgtat ataaatggcc aataagcacatgaaaagatg ctcaatatca ttagtcatca 31440 gggaaatgca aatcaaaatc acaatgagataccacttcac aataggacag ctataaagac 31500 agacaataac taatgttggc aaggatgtggtgaaatcaga actttcatac actgcagtta 31560 agaatgtaaa atagtggctg ggcgcggtggctcacgcctg taatcccagc actttgggag 31620 gccgaggcgg gcggatcaca aggtcaggagatcgaggcca tcttggctaa cacggtgaaa 31680 ccccgtctct actaaaaata caaaaaattagccgggcgcg gtggcgggtg cctgtagtcc 31740 cagctactcg ggaggctgag gcaggagaatggcgtgaacc tgggaggcgg agcttgcagt 31800 gagccgagat tgcgccactg caatccggcctgggctaaac agcgggactc cgtctcaaaa 31860 aaaaaaaaaa aaaaaaaaaa aaaagaatgtaaaatagtgc agtcactgtg ggtgcagcgc 31920 accagcatgg cacatgtata catatgtaactaacctgtac attgtgcaca tgtaccctaa 31980 aacttaaagt ataataataa taaattaaaaaaaaatagtg cagtcacttt gaaaatcagc 32040 ctggcagttc ctcaaaatgt taaatatagagttagcatat gacccagcaa tttcactcct 32100 aggtatatac ccaagagaaa taaaatcatacgtccatggc caggcgtggc agctcatgcc 32160 tgtaatccca gcactttggg aggctgaagcaggtgaatca tgaggtcagg aattcaagac 32220 cagcctggcc aatgtgatga aaccccatctctactaaaaa tacaaaaatt agtcaggcgt 32280 ggtggcgcac gcctgtaatc ccagctacttgggaggatga agcaggagaa ttgcttgaac 32340 tcgggaggtg gaggttgcgg tgagccgagatcatgccact gcactccagc ctgggtgaca 32400 gagcaagact gcatctcaaa aaaaaaaaaaaattaaaata gtatgtccaa aaacttgcac 32460 atgaatgttc atagtagcat tattcataatagccaaaaaa tggaagcaac ccaaacgtcc 32520 accagctgat gaatggaaaa gcaaaatgtggtatatccat acaatggaat cttatccagt 32580 cataaaaagg aatgaagtac aaatagatgctgctacaaca cagatgaacc ttggaaacat 32640 tatgctaaat gaaaagtgcc aatcacaaaagaccacacat tgtacaattc tctagatatg 32700 aaatgtatag aatatgcaac tctatagccaggcctggtgg caggcatctg tagtcccggc 32760 tacgcagaag gctgaggcag gagaatggtgtgaacccggg aggcggagct tgcagtgagc 32820 caagattgcg ccaccgcact ccagcctgggcaacagagcg agacttcgtc tcaaaacaaa 32880 acaaaacaaa acaaaacaaa agaatatgcaactctatgga gacataaagt agattagtgg 32940 tttatagggg atgggggaga gaggaaggcagaatgactta caggatttct ttttgggatg 33000 atgaaaatgt tctggaatta gatagtggtgacggttgcac aactatggat atactaaaaa 33060 acattgaact gtatacttta aatggatgcattgtatggta tgtgaattgt atcttaaaag 33120 ttctgtttcc aaaaaaaaag tcagatggggctgtacttat ctgaaggctt gactggggct 33180 taagggtctg cttccaagtg gctcactcacaagaatgtta acagaaagcc tcagttcctc 33240 cctcaccaca tgggcatctt catagggctgcttgaatgtc ctttttgttt tttgttttgt 33300 tttgtttttc ttttgtcttg tttttgaggcagtgagatcc tgcaactctg ttgcagttgg 33360 agtgcagtgg tacaatcatg gttcactgcagctttcacct ccagagcaca agcgatcctc 33420 ccacctcagc ctcccaaata gctagaccacaggtgtgtgc cactataccc agctaattgt 33480 ttttgttttt gtttgtttgt ttgttttttgagacagggtc ttgccatgtt ggtcagcctg 33540 gtttcaaact cctggcctca agcaatcctcctgcctcagc ctcccaaagt gttgggatta 33600 caggggtgag ctaccacacc tggtcctgcttaaatgtctt tgtgacatgt cagctggctt 33660 ccacagagtg agtcatccag gaagaagagcaagaagtcag gcacaatgcc ttttatgact 33720 tagtctcaga agttacctca cttccatcacattttatttg ttagaagcaa gtcactaagt 33780 gtagctcata ctcaaggtag gggaattaggctccaccatt tgaaaggagg agtatcaaag 33840 aatttctgca catcttctta aaccaccacagcttctaatg ttgttctgtg acctagaatg 33900 atttctgtag tgtccctgac tccccatctctctctgtctc ttttattcta gtttaataag 33960 ctattgaatt gaataatgtg tttcttcccatctactgaga tgtttagttt tagacacaag 34020 ttgtgtctca ttctttattc cctcatacttagggctgggt ttcattgatg gcaggtatgc 34080 taggggctga actacctgga aatgttacaggcatggtcct atagccatag atttgtactc 34140 cataacccta ggatctcctg gaagaagactgccttctggg cttcctcccc agatgccaga 34200 ctctgtctgt ctcactgggt ttcctctcctggtctgcagt gggggctgcc ccagccaaat 34260 gggtgcgtac gttcccagat gtggcagcagtctcctaaca acctccagcc agagcaccat 34320 caggatctgc aaagcagagg ccactgtcttcctgggaagt ctgccagcca atgtctgggc 34380 acagctggga cactagggct tggccatttctgcccaattg ggactcttct acaggcagtc 34440 tttgcaccag agctccctgt tggctggctgagactttttc agagtggcac ttcaacatga 34500 ggctcttctc aaccaaccct ccttcccctctcttcccata gatgtcagat ctgaaacaca 34560 gtcggaaggc tttccctgcc cagtcctgcttcttccccct ttatctttca taggcatttc 34620 ctctgatgaa tctcttggac ttctaactctaggttggcag cagtttccta gaggacccag 34680 ctgacaccct ggccctggcc cttttctgtggctgccagat cccagttccc tggggcatga 34740 gttccctctc cacccctcct gaccgctctattccctcttc cttcctctct ttcgcaggct 34800 gtgtccacag tctcaacctg tgcctggcacatagtagatt cagtaactac ttgtttttga 34860 atggacacag aatactctgg agctaggcactgcccccccc attctcctgg catagagagc 34920 cacagagagg cccctgggta aggctgggagtgccagctcc atgggccaga aggaaggcac 34980 ccttcaggcg actggggaag gaaggcctgaggctaggagg ctgtgggaga gccaagagac 35040 tcccagatcc cagggaggcc ttcctcacatgccaggggaa gtcgaagctg gcttctctct 35100 ggatctgctg ggtgagcaag tcactccttttcttgggcct tactccatac ctctatggga 35160 ctatgggatg agaagcccca ccctgcctgtctccctaggg agaggcaggg gtagtgagct 35220 tcaggtgaag tcatgtctgg gaaaacatgaatgggaaagg gcagggcaca cggggtttgg 35280 gggtttgtgt atggggaagg atggtgagagacagggatag acgatcacac agggaagaag 35340 gagaggccct gcccctcctt ctctcatgaacccccacccc tactccccac tggcacccac 35400 tatgcaccct gcctcaccca gacaggtggagggccagaga aaagcctcag accctcttcc 35460 gtctgcagga cccaggcctt cctgtctcgctggtttggcc cctctgctcc agggcctctg 35520 agggacaccc tggtggaagg caggactctgagcctgtctt gtggctgact gacttgtttt 35580 tgggtggagt ctggacagaa agctcagtgacaccctccct cgaggcctgg gcaagcccca 35640 gcctgatgtt ctttgagacc cagactggaaaagacctcaa agttcaactc cactgtactt 35700 ctcactgtac agtgggggaa actgagtcccagaaagggac agggacaagc ctggagtgac 35760 ccaggcaggt agtgtcctgg ccactgttcccacagttgcc atctagcccg agctctcaga 35820 tatcacagat gctgtggccc caaaatcttgggacttgctt tctcctgagt aaactgcttc 35880 ctggccaggg gtatcctgag gctttagtgatggtgttttg ggtgccagga actgtgctgg 35940 gaatcttacc caacatcctg tggagtgactactgtgatta tgcccatgat acagatgagg 36000 aaactaagac tcagagaagt taagatttccaagcctaggg tctgtgtgga aacctaagct 36060 ggacctgtct gacctcgaaa gcttggctcctcgtatccta cctcccagcc tccccaggtg 36120 atgggcaggg aagggctcag caatgtggaaaagggggcag aggtgggtgg cagttcctat 36180 gatgggagga agtctcagca tgatgatttttcaaacatca caactcttca cagaaggact 36240 cacctttgtt cagctacatc cttgcccttggggaccccag gtctacctcc tctgccacca 36300 ctcgctgtat tccacacccc ctttctcaacctctggcaag aaggcgcttg gtccctggac 36360 tagccctacc ctctttccct tctcttcattgttcccagct atgatgcttt gagccacagg 36420 cccaggctgg ttctgaagct acagagatggacctgcccac cctgcagccc ccttccccct 36480 ctgccacaca gtgagctctc cttccccagctctgcccctg gctttacctc actggggctc 36540 atcccctgga agagactcag atggagcctggggcaggggg aggctggaga agcagcaggc 36600 taatgggcag atggaagaca gacaagtcactgtcctggcc agccctgact cccatccaga 36660 tccccaagcg ctgcattccc atcctctaagccctccccag ctggagcctg tcacctgagg 36720 ttttcccacc ctcactgagc ctcagtttcttcatctgcac tatgggtgta agcaccctgg 36780 cctcactaga tggttggaag ctgggctttgggatccagga acaatacctg ggtatagccc 36840 cttcctgatg gagagattcc tgtctcatgaggcacacatg atgcctgctg tgtcccccca 36900 ggtggccagg gatggaggtg gccacagacatacaccctgg gccactctct gccactctag 36960 ggaccatagt tctttcaaat ccagagcatcagccctgccc tgtgtggctc tcaaggcctg 37020 ttcccgctgc gtctccccca gttatcagaccaggagggtt gctgcaaggc caggcccatg 37080 cttggagtcc taggaagcgg ggagccctggggctctgtcc cctgagtatg ccgagagcct 37140 ttctaagaac caggacttgg caggggagcaccccaggtgg cactcccttt cccagaagcc 37200 ttgggaactc ccagggtggt agcttcagagccccagccct tccttcaccc agccctggca 37260 gaggcccatg gccccctgcc agcctgatggaggtggatgt ggcagccacc gctgtggtaa 37320 gggtgagaag ggtgggttct aagggactcctccaagctcc tgaacccttt tccttccctt 37380 caaggagatg tgaaagcccc agcctggtccccatcccaca gcttagggct ttggctccca 37440 tagtcccaat ctaggcaggg ctggcagcaggtgactggat ggtgctgaga aggcaggcag 37500 aatgggggcg tgggccctgg caagtgcactcctcagccaa tcagcgtcct gcccggctgg 37560 tggattcggt tacaagccca agatcaccccatactccagc ctctttcctc ctcctcccgc 37620 agctccattc attggtcccg ccgcaccgggcctgctgggc tccgcttccg ttccactgct 37680 cagctgccgc ctggtggggc caccaagggcaggcatccca ggggctttgt ctgactggac 37740 tgggccagtg cagaatgggg gttcaggcagggctgtttgg gatgctgggc ttcctggggg 37800 tggccctggg gggctcccct gccctccgctggtacaggac ctcctgccac ttgaccaagg 37860 ccgtccctgg caacccactg gggtacctgagcttcctggc caaggatgct cagggactgg 37920 ccctgatcca tgcccgctgg gatgcgcataggaggctgca gtcatgtagc tgggaggatg 37980 agccggagct caccgcagcc tacggtgctctctgtgctca tgagactgcc tggggctcct 38040 tcatccacac ccccggaccc gagctgcagagagcactggc cactcttcag agtcagtggg 38100 aggcatgccg agcgcttgag gagagtccagcaggggccag gaagaagcga gcagcagggc 38160 agagtggagt ccctggtgga gggcaccagcgagagaagag aggatggacc atgcctggca 38220 cactgtggtg tggagttgga gattctgctgggaactcctc ggagctgggt gagccatgag 38280 gggtgtgtgg gctggggggt ccgatcggggaagcaaggtt tcttcagccc cagcccttac 38340 tctcctaggc tgtgtgtccc tgggggagtgacttgaccat ggtgaacctc aatttcctta 38400 tctgtaaagt gggggcaatc acgaatctcatcatggggtg cttaaatgag gtcacggttg 38460 gggaaagtct tattcaaacc tgggagtcctcattaaatgc catccgaggg actgggcagg 38520 ctgggggagg atccagggtc aactgagccaaaaagccatt acccaggagg aggctttgtg 38580 ggcacggggt gcccagtgga atggatgctgagacgaaagg cctgggttca aatcccaact 38640 cagcacatac aagctgagca agtcacttcccctctctgga cttatttcct cacctgtaaa 38700 atgaaggtga tacctccctt tcagggctggctgtgaacct ggatgtggga agtgccaggc 38760 atgtgggaaa tgcttagtaa agagtgctattttttagatg gtaataaaca tagatgaatt 38820 tcttgcacta tcagtacaga tgtctgtgcgtttgtgtgca gggttggggg agggcttggc 38880 acctgagtca gagtaggttg gcatcctggcgacacctcct tgtgccagtg agaaaggttg 38940 caccctgcct gtttgccatt ccatcatacacacattcata attttggagt tttatttggg 39000 gcgtgggctt gggaactctg gaggcagactccaattcccc tgaggaagac ctttccatgt 39060 atttatgggt gggctacctg gcatttagagttgcccaaca gaggctgcag cttggcttct 39120 cttttccagc tttgaaactc tgagagtcccacagaaggga gagtgactgg tctgaggacc 39180 ctcatggcgt ttgtgtcagg gctggggtgagaaccaggtc tctgccctct tcctaccagg 39240 ggggcatagc tggtgcatga tgcctaggaccctgctgagt tggtgccctc tcccctcccc 39300 tccctgcagg ggtcttccag ggacctgatctctgttgccg ggaacatgac cgctgcccac 39360 agaacatctc acccttgcag tacaactatggcatccgaaa ctaccgattc cacaccatct 39420 cccactgtga ctgtgacacc aggttggtggcaggcagcga gggcccagag ctcagggaca 39480 gggcagagtt acccagttcc tgggtaactagacattggga ttgcagagga tcttaaagct 39540 cagccagctt ggaccccaca gtgcaggtaggaaagctgag gccagaaaga agggatgctt 39600 ggaccccaaa ccacccagct ggtagtggcacagtgggctg tgggaggagc cagacagccc 39660 tccatgcccc agggtcctgg gtatctgttctggggcaggt ttcagcaatg cctacagaat 39720 cagcacgact ccatctcgga catcgtgggcgtggccttct tcaacgtgct ggagatcccc 39780 tgctttgtgc tggaggagca ggaggcgtgtgtggcgtggt actggtgggg cgggtacgtg 39840 gccaccccct catgtccctt tccagacagagagggagccc aggctccaag cctggtgagg 39900 gagagctatc tgtctgtctg tcttccagggaatgatgtcc catcctgcat gtcctctcct 39960 gagggcccgg gatgcagacc ctccttgggtgtcccccaca acccagcggg atgggggatg 40020 ggactggcag agcattgatc tccatggagacgaccctggg ggcttctgga agggggattc 40080 ccagtcacca atttccacca actgccaccacccaggtgta ggatgtacgg cacagtgccc 40140 ctcgctcgcc tgcagcccag gaccttctacaatgcctcct ggagctcccg ggccacctcc 40200 ccaactccca gctcccggag cccagcccctcccaagcctc gacagaagca gcaccttcgg 40260 aaggggccac cacatcagaa agggtccaagcgccccagca aagccaacac cacagccctc 40320 caggacccta tggtctctcc caggcttgatgtggccccca caggcctcca gggcccacag 40380 ggtggcctaa aacctcaggg tgagctcagaacctaacctt gggggttcct gacatgaggg 40440 ggtgtccctg cttctgttta ggggtggccatgtgttgcct cttttcctgc accagtttcc 40500 tcctgggatt tcccaacctc tcccatgaaatcacactgca gcacaggatt ttcataatcc 40560 acgaatttga ccacatcagg ccccactgtgcacccaccac cactcctctt tatctcagcc 40620 aatgatgtcc caacacccag aggccctcaagccttggccc tgcagaccct acccccagtc 40680 aaaactctag tttcacaaac ttcacttggttcctcaaaag cgccaggctc tctcctaccg 40740 tgaggccttt gcacatgctg ttcctcctctccttgtcttc tctcccaccc tcagtttagc 40800 agcctatgcc tcctggaagc ctttcttgactaccgtcagt actctgggtg tcccccatag 40860 cagtactacc gtgtttggcg gcttgggggtagggaggcac tgccacaagg gcggcacact 40920 gagggcacaa agactcagaa ggcatgaaatggagggaatc tgtgtgtgtg actgagcaca 40980 cgtgctggtg tttctcccgg atggcgcaggcattggtggg gcctccctgg tggattgggc 41040 tcccatcaac accacatcca cccctcaggtgcccgctggg tctgccgcag cttccgccgc 41100 cacctggacc agtgtgagca ccagattgggccccgggaaa tcgagttcca gctgctcaac 41160 agcgcccaag agcccctctt ccactgcaactgcacgcgcc ggtgaggccc ctttgaaccc 41220 tcgcggggtg ggctgcctgc tgccaggcatgggaaggggc ccctggctgg caaggccctg 41280 ccccggcctg agcctgcctc tgttctcagtctggcacgct tcctgaggct ccacagccca 41340 cccgaggtta ccaacatgct ttgggagctgctgggcacaa cctgcttcaa gctggcccct 41400 ccactggact gtgtggaagg caaaaagtaagtgatgtcag agccaggagg gatggggggt 41460 tttctcaaag ggtgggttgc ctatacccactttgaatgct tgggccaagg ggtaggggaa 41520 gggatccgga gacctctgag ctcctatccatagcctcatc cctctacccc ctgctgcccc 41580 aggtccagct ctgcagttgg cctctatgggtcgcatcttg gctttgtcat ttgattccca 41640 catgaccttg gcaactggtt cacctttccaagtttccatg tctttgtctg taaaatggtc 41700 gtaggaacca aggaaacggc aggatgcacataggtcatgc cccgcctggc acacagcaaa 41760 atgtgtactt aactcactcc taatccacaatctcatttgg tcttgaactt ctggactcga 41820 gcgatcctcc cacctcggcc tcctaaagtgctgggattac aggcgtgagc cactgtgctc 41880 tgctttcatc tggattccga ttctcaaagccagctccttc ttaactttcc catttcatag 41940 atgaggctga ggcttctggc tcaggtttccacagccagct agtggcagaa cccaggcctc 42000 caggtaccag cccggtttat tataccctttctccgtgaaa cccacccctc tctgccttgc 42060 tggtgactgt ggccccagcc ccctctctctctgggcctca gcccactgtc tgcagagtaa 42120 ggtgggatcc ttgtcagccc tgatcatctgccccactctt ctctccttac agctgttcca 42180 gagaccctag ggccatcagg gtgtcagcccggcacttgcg gaggcttcag cagaggcgac 42240 accagctcca ggataaaggc acagatgagaggcagccatg gccttcagag cccctgagag 42300 gccccatgtc attctacaac cagtgcctgcagctaaccca ggcagccagg agacccgaca 42360 ggcagcagaa gtcctggagc cagtgacctcagtttcagct ttcctgggca ccagcctgga 42420 ccttgcccat ggctatgcca agccttgggaatctcagcct cccctccgta ggttagactg 42480 aagcatggca gaggctgttg tggacaatcaagaggatgaa tggggggatc tcaaggccca 42540 aatgctggac cacatctcct gctgttctgggtaaccttga gctatgtatg acacaactct 42600 tctatgcctg gatgtggtgt tcaggaagctcattctgatg ccctgggctt tggccttgcc 42660 agggaacttc acatacagat gagaatggggaaagggtaac ttattgcagc agccccaggc 42720 agtaccagga ggaggtacat gtatgtccgtgttgcaaaaa taatacatgc ctcaaaaacc 42780 tgcctagggg agccctagtg cctgggtgctgtggcctgag gtagcaggtg ggaagttagg 42840 gatgtcacag aaatgtctgt gtctgaatccaggattgggg tgggtgttgg agagggcttt 42900 cagctcccct cctcccaggg gggcctctttttttaacggc tgccgtgccc ttcctggccc 42960 agccctaaac ctaaattcaa atctcctccatgcctttgcg caaaggacct ccctcttgca 43020 ctctaagcct tagtttcctc ctctaaaaaaagggggtctc taaacaggag ctacctcata 43080 gggttgttga ggattaagtg aaccaatacatatacagtgc ttagcactta ataagtattc 43140 ccccctgcga cacctagctg aactatggtttggtgtctga tcttgagagg ttgatgtaac 43200 cttttaaagg cctcagttcg ctcacctgtgaaatgggtct aagaatagca ctgatctcac 43260 agggttgtga tgcagattaa aggagatggcatgtgtaatg tatacagctg gtgcctggta 43320 aatgtcggtt ctgtcattcc ctcacctcttcagtccctgc ctctgactac caccatccca 43380 agactactaa caagtaggaa agagccgagagtgaggctgg agaatttaat tcctaatgga 43440 tgacctccag gattgggaca tctgccagagctctcccatc atcccagatg ggggcctggg 43500 tggggctttg ctgattgtca cagttgaggtgccaggactg agttttgggg gaccccagtt 43560 gtccacccct ggccaggaca gagaggcaggtgcagataca gctggaggag cagcaggaga 43620 gaggcaggtg ggcttgcaaa agattgaggcagaatggtgg tcaccttggc ccatctgcct 43680 accccaccct cagggcccca ggcccccttcctccagcccc cgatggccct ggggactagg 43740 agacaggctg ttgggcgcca gggcctcccgatcaggtccc caggagccac caccaccagg 43800 gtctacagtc tctaggcgca aggcgggcaacaggcccagg cttcgaggca cagctggtgg 43860 gaaggcccag gggccaggca acccagagggcccctcttca ctactgcccc ggctgctgcc 43920 attactgctc ctgtcaggag ccactcgggacaggcggcgg ctctggggtg aggggctacg 43980 gctggcacca cggcgttcac gggatgagggccgtagggca agcccaggga acctggccag 44040 tcccgggctg cggctgcggt gtcgcttggacttgccagga ctggggctgc gggacttggg 44100 tgcaaggagc tccagtgtgc tgtcatcctctccctctgag ctggtgcctg agctgtctgt 44160 gctgctgctg gccaactccg aggaaggcagcgagatctgg gggaaatgct ggtcactggg 44220 gcgccctgct ccccaaccca gccactgaggcctgacctcc cgaggtctgc ctctctcgtt 44280 ggcagatctt gggaggtcag gttatttgtctgaactcaag gagcagaatg tagaggctgt 44340 ggcatttgac aaaagtcttt aggcacccccagcccagcag tctggcctac ttacctggaa 44400 gggttcagtg atgccgatga ggatgctgtggttgtgacta tagtagccca ggatgaagtc 44460 tccatggccc ttgggcagtg attcctcactgaatgttacc tggtaggccc aggggtataa 44520 gcctaagttg ggggtcaggg aggccacctgagagccccca aggtgagttc tgaggtccca 44580 aaggcaacaa ggacttgccc tgactctcccactcctttta agtacctggt aggtattccc 44640 atccacatct tcatgtttgg cccagacataagccacatag tccttgcaat ggcggaaacc 44700 cacctggggg atcagtgttg tggaatcagtgttgtgaccc tataatgtct gatcccagca 44760 gtctcccagt gtggcatcaa gatctggacaagccagtgac cccaccatgc tgttcagctg 44820 ctcctccagg cccctttctt ccctgagtcgctgaccacca ctgcccctct cacccggtat 44880 aagccgatcc agtcccagga gctgcgggcgaacactgttt ccatgcggta cctcaccacc 44940 gcctgctcgg gccgcaccca ctcatctgccacctccagcc gcaccagtgg catgtcgtcc 45000 ctgaaggcaa actgtccagg caaggcaggggcagggggcc acatcagggg agaccctcta 45060 gtatcccaca cacttaaggc tcttgggtcttagcacaaat tgcctgagac aaagggccac 45120 tttacagact gggaaactga ggcagaacaggtctagtata aataccaagc cctgtgctgc 45180 ctcccagccc agggttcctt ctgcccacagcctccttagg gagtgagtga gaacatagct 45240 ttgaagctag caaatcctgg atttggctctggttctgccg ttgacaggct gggtgagttc 45300 ctcagcctct ctgaatgcca gggccctcatctgtaaactc agagactctt tttttttttt 45360 ttctttttct gagatggagt ctcgctctgtcacccaggct ggagtgcagt ggtgcaatct 45420 cggctcactg caacctccac ctcccgggttcaagtgattc tcctgtctca gcctccccag 45480 tagctgagac cacaggtacc gccatcacgcctggctaatt tttgtatttt tagtagaggc 45540 agcgtttcac catgttggcc aggctgttcttgaactcctg acctcaaatg atccacccac 45600 ctcagcctcc caaagtgctg ggattataggcatgagccac cgtgcccggc caaactcaga 45660 gactcttatt ttactcttgg agttgttcagcagattcagt gagacaccat ttgcaaagca 45720 tcccataaat ttcccagtat accagtaagtgctcaataaa tgatttgtct ctatgctagc 45780 aaggaagacc aataaaatcc tatgatgcactgggtatttg gggtaagctg aatattcctg 45840 agcaggcaag aagagctctg cgtgggaggatggagacctc agtccacttc caggctctac 45900 tgctaactcg ctatgttacc ccagggcaggctctaaccat cccaaggttc agtttctcca 45960 actgagtcta agtactaagc ggttactaactattaccttg tcatcagtcc atgaaggaaa 46020 gttataacca cgagtatcct ttccccaaggtcaacccaga cccaccaggg gcgccacctg 46080 aatgggtgga gctgctgagg tggcaggctgccaggatatt gaccccacct ctgtccctca 46140 gggaaggact gagttgttgc caacaccagatctttgtctg atcccctgtt tacctagttt 46200 caggtttccc tccctcagct tccgagccaatctgttccag aagtaactgg cacattcttt 46260 ccctgttcct gtgttcctaa cagcaggggcgggcaagggt agacctttga aaatgccctc 46320 caaggccttg cagcatcaaa acccctactgagccctattc tgactgcatt gccttggcta 46380 agagacttaa gttctctgag cctcagtttccctcaccagt aaaacagaga ggaaaactgg 46440 gacatctcag ggcctactga ggcattcaaaaggatgacat atgtaaagtg cactacacag 46500 gcctggcatg tagtaggtac tcaatgggaatttttttttt ttttttgaga cagagtctcg 46560 ctctgtagcc caggctggag tgcagtggtgccatctcaac tcactgcaac ctccgcctcc 46620 cgggttcaag caattcctct acctcagcctcccgagtagc taggactaca ggtgcgcacc 46680 accacaccca ggtaattttt gtatttttagtagagagagg gtttcactgt gttggccagg 46740 ctggtctcga actcctgacc tagtgatccgtctgcctcag cctcccaaag tgctgggatt 46800 acaggcgtga gccactgcac ctggttgggaaatgttttta aagggacaga gtcctggagg 46860 aggtgggaag gacaggatgg ggtgtcaaaaggagtgattt ttcaggtgag gtccctaatt 46920 gtgggttaaa tcttcatgcc caacacttttgccagaggtc atggcaggcc aagcgtgggg 46980 atatttccat tcccagctaa agatattggccaatgtccca ctgactggcc atgtgacaaa 47040 gttaccagga aaaacatttt ctggcctgctgggctccctc ttatcagatc aagagacttg 47100 aagagcccag agttgggttt cagggctgaaaagatgggat ctaccctgct ctgccactgc 47160 agagcctgtg tatggtttgg ggcatgtgcctaccccatga ggagcctcag atcccgccac 47220 agaaaaaaag ggagtgggcc aaattggtctcacaggtctg gttctgagat tctaggattt 47280 cccattttga tgtcggcaac caggaacctcaatcctaaat acaatataaa ttatagtaac 47340 tacttaagag ttcagctttg tattttttatatctttgctc tccctcccca tcactacaca 47400 ctctcataat gcttggcata tggtaagacagttaagtact cagtaaataa cgaatgaatg 47460 aatatgaatg aatgttacat ggagtttgattttgctggtc ttattatata tgtgaatttt 47520 tatatctttt ctttgttatt tttaagacactagtagtgaa aatgatgatg catatgtgaa 47580 tttttttttt tttttgagac aaggtcttgctctgttgcct gggctggagt gcagtggtac 47640 gatcacagct cacagcagac tagatcttccaagctccagt gatcttccca cctcagcctc 47700 ataaatagct gggaatacag gtgtgcaccacctagctaaa ttttattttt atttttattt 47760 tttccctgag acacagtctt gctcatgtcacccaggctgg agtgcagtgg cacgatactg 47820 gctcactgca acctctgcct cccaggttcaagtgattctt gtgcctcagc ctcccaagca 47880 actgggatta caggcatgca ccactgcgccaggctaattt ttgtattttt agtagagatg 47940 ggtttcgcca tgttggccag gctggtctcaaactcctggc ctcatgtgat ccgcccacat 48000 cagcctccca aagtgctggg attacaggcgtgagccactg cgctcggcct ttttttgatt 48060 ttttttaaag acagtgtctc actgtgttgctcaggccggt cttaaactcc tgagctgaag 48120 tgatccttcc acctcagcct ctcaaagtgttgagattaca ggtgtgagcc actgcgccag 48180 cctataaatg aattttaaga taaattactctaaacctttc tcagaagaca ggagttagag 48240 attagcagaa aaggcacggg ctctaaggctgggtgtggtg gctcacacct tgtaatccca 48300 gcactttggg aggccgaggt gggcagatcaccggaggtca ggagttcgag accagcctgg 48360 ccaacatggc aaaaccccat ctctactaaatacaaaaatt agccaggcgt ggtggcgggc 48420 agctgtaatc ccagttactc aggaggctgaggcaggagaa tcacttgaac ccaggaggta 48480 gaggttgcag tgagccgaga ccacgccactgcactccagc ctgggcaaca gagtgagact 48540 gcattaaaaa aaaaaaaaaa aaaaaagggcgccgggcaca gtggctcatg cctgtaatct 48600 tagcactttg ggaggctgag gtgggtggatcacctgaggt cagcagttca agaccagcct 48660 ggccaacacg gtgaaaccct gtctctactaaaatacaaaa attagccggg catgacggcg 48720 ggtgcctgta atcccagcta cttgggaggctgagacggga gaatcgcttg gacccaggag 48780 atggtggttg cagtgagcca agattgtgccactgcactcc agcctggggc ggctgagcaa 48840 gactccgtct caaagaaaaa aaaaaaaaaaaaaaaagttg gccagacacg gtagctcacg 48900 cctgtaatcc cagcactttg ggaggccaaggtgggtggat caggaggtca ggagttcaag 48960 accagcctgg ccaacatggt gaaaccctgtctccactaaa aatacaaaaa ttagcctggc 49020 gtggtggcgg gtgatgtaat cccagctactcaggaggctg aggcaggaga atcacttgaa 49080 cccgggaggc ggagcttgca gtgagctaagatcgtgccac tgcactccag cctgggtgac 49140 agaatgagac tctgtctcaa aaaaaaaaaaaaaaaaaaaa agaaaaggca tgggctctga 49200 aaccagactc acttgggttc aaatcctaactgttcctctt actagttggg tgaccctggg 49260 caggtgatgc catgtgtctg agcctcagcttcctcatctg aaaatgtaga ttgcaacccc 49320 atttccactg ttacaacaaa tggatgctgctgagggcagg tacaaggggt tatacaaagg 49380 gtaatggtga ggggcagtgg tatgccgagttgggcctggg gatttcatgc ggggaggatg 49440 aggccagaac tcacctgcag gaggaactgggcagccacag gcttgtggtc gctgactgtg 49500 tattccatgt ggctgcggta gctgtgctgcgtcacctgga gtcggtggct cttccgtcct 49560 gaggggctgg gacccccacc tggagccttgaccttccata ggatacggtc tgtccaagct 49620 ggcttccgtt tcttggcact gcagtgagcaggggtacccc aagtttcagg ggctggggat 49680 caagatgtaa ccctccacct tgcctcctgcccctcttccc aaagtctccc tgttcgagaa 49740 gacctcagcc cacttcccct cagtccctcctcggactgag ctcacctggt atcgtatttg 49800 ttggtaccca catcaaactt gaaggtgggagcgaagttga ggggcccctc ctgaaagccc 49860 ttcagaatgg gccaggtgtt cttggccatgttgagctgtg gggggtccag gagagcagat 49920 tggacaacag cttgggctct gctgtgcccagggagggggt ggggcaggtg aggacaggga 49980 ccatagtcta aggtacaggc gtgtcctgggacatgctctg tgtgcttctg gggacaagga 50040 ccccacctgg tccttctccc agagctgatggagctggtca ctgtcgatgg caaacttgac 50100 aaagtgcagg tcatagctct caatgcggaagttcaggtcc ccgaaccaga acacgaggct 50160 gtttggggtg ggggatggga gagatgtggggggcagtggg gggtgtcaac aggtccatgg 50220 aggataaggg ctcagcccag atccttccagcccatccaac ccgaggggat gtagtgagtg 50280 ggtgagtggt gccagagcct ccagcccaccaaagggcaga ggaaaagcag agggaccggt 50340 ctacaggaaa ttaggttctg accttcagcaaggcggggcc cctcagcaaa gctccaccct 50400 acaagctccg cccctcccca tccaactgctctctgctttc gtgttcctac aactagtttg 50460 ggtgggcact aaaccccata ggccctgcctctctccataa gccccaccca aggtggtaca 50520 aaaaccccca tcactagccc cacccaagctctatttggcc ccaccccagc ccatactcat 50580 gatccaggat gccctgtgcg cccggcccttggaactgctg gaggctgagg atggtctgga 50640 agttgtcttt gcgctgctcc gccttgtccatatgcgcagg caagtggcag ttcaggaagc 50700 agagcatgtg cccgaaggcc gccaggcgcacgctcacgcc acccttgtta ccctagggag 50760 gcagggtcgg atggctcatg ggcggggcttaggccaggag gtgaggcact gggagcgggg 50820 gttagagagg agatgtgggt ggaaggtgggtgggtcctac agaaatgagg aacaacgctg 50880 ggacacagtg gggagagaaa agggcgggggtatagaggaa taggatgggg tattgggtgg 50940 tgcatggggg ggctgggccg cagggtaaagggtggaggat gggaagggga ccttgctgtg 51000 catggggcgg ggggactaat ctaaagcccccttcatgtcc catcctcttc tgggcctgct 51060 cacaggctca cccagtagcc gcccaggccagtgcgcgtgc agtcggtctg cacgtctcgc 51120 aggaagggca ggtggtagta cttggcgaacagcagcagga tgacaccctg catcctcacc 51180 gaactcacct gcagcgggag gccacgtggctgggggacag aacacaactc ccccgccctc 51240 gcgcccacct tcaggtctgc tcctccacccacccatgtca cggacccagc cacagaggcc 51300 cagcgggccc cacagtgagc cagggtacagctggagccag gaattcagca gggtctctgg 51360 ctgtccaggg ggtgaggggt gcgttaccagcacgaagttg aagggcccta gcgcatccat 51420 gaacagctca ctccactggt ccgtgaagagggcgtccttg agtcgcttgt tgagcatgga 51480 gttcacttcc tgcaacctgg aggggtgggggcagggtggc catgggattg gagaggtgcc 51540 ctggaagccc ctgccatggg tggagggcccggaaggcccg aggggctcag gagggggtcc 51600 acatgccctg ccacctcacc ctatggcgatcatgtctgcg ccgtcgctgt cgtcaccacc 51660 gcccaggtgg aggagggatg tgacatcgtctgggggcatg gcagtgccca cgttccatgt 51720 gaccacagtg atcctgaggg caggggcatatgagggtgta gtcctggcac cactccctca 51780 ccctcaagct tcctttcaca ggactccctggggaactaaa tggaggcagg tgtgggccaa 51840 agccctaaga aggacccaca ggaggccccgaatcctgtcc ctctgccaca ctctccctgg 51900 ggagatcaac tgagaggcgg caagttccttaggaggggat gctatcttct gagcgtcaca 51960 gagtgggccc agcaaccccc tccccaaagactcttcctca gagagagaag ctgaggtaga 52020 gcacaccatc caccctggaa gaatggctaacctcagagct aagccccagc cacctttctt 52080 gggagagggc cccctcaccg gaagccggggtcgctcttcc aggtaggctg agctgaccaa 52140 ggggaggatg acagggtgga tgtagaagaggaggtggtga ctggggctgg ggcttcttgg 52200 gcctgaaggt tggggctcag gcacctgccaggccctgtac tctgtgtgcc aagccttggg 52260 agggccatgt caggggctgg gggaacacagggagagcgat tcggggagtg gcttggggaa 52320 cggctgggtg atcggggtgg cttgggcagaggtgggggca cagtctggcc tgagggggcc 52380 ccaggccgga aggtggggga cagaagtccaggggagtgag tgccaggctc tgaaggaccc 52440 tggcccacat ccaagggcaa ggtctggggtggccgtggca aaacaggatc ctcagggctg 52500 ctgtggaggg cctcaggccg ggctcggaaggagggggaga gccgagggtc tggggaggtt 52560 tggatgcagg gtggggagcc tgtaggaccagatgtctgag ctggaggctg gagatgcccc 52620 tcagaagcag ggagaggtct aggggctggggcatccctct ttctagctga tgtctgtccc 52680 acagaggctg cgcctgatgc cgtggatgctggagccaggg cctgttcctg agttggagac 52740 agaactggac tgggcaccgg ggaaggggtggaggggagtt ctgggggctg ctcctcagaa 52800 gccagggcca ggctcaggcc agaggctgccagtgttggct tgggtcccac ggaggcaggt 52860 ggctcctgct tctggtctct ggaggttggggccagattgg gccccagggt gactggggga 52920 gatcttggcc ctgctgaggc aggcatcaccagccccaggg acgtcggagc cagaactgag 52980 cctgtggtcg ctgggggagg ctttggtccagctgaggcag acatcaccag ctggcccaca 53040 gatgttgggg ccaggctgga gctgcggtgggcagtagctg ttttctgccc ttcaggggta 53100 cacagtggag ccaggattgg tcggggagatgccagagcca gcctcggtcc ttccgaggaa 53160 gctgacatag ctgcccgtgg ccctacaggtgccagagcca accttggttc cgagggtcct 53220 agggctgcgt tcttctttgc tgggagctgaaaacttgagt ccaccttgtg gaggacaagt 53280 caaagattca gagtgaccct aaccagggcattgggcccca acttccatat agaccctggc 53340 agagttcatc tagctaagaa aggcacatctttccaaggaa gttcttccta ctatctcact 53400 tcaatctatt ctgctgcagg tcaacttctgtcttggagga gataggacac aaaaccctaa 53460 cccctccttt aagtctgaaa cctctttcacagatggggaa actcagaccc tgactcaaat 53520 gaggcagagt gtgaacctaa acctgaggacttgccttgcc ttcctggctg gcacccacac 53580 cctgcccatt cggggcagct tccctgggcaaccctcccac tgcagtccct gaagctcccc 53640 cagccacggc tactgacctg acatcccaggtctgggcaca ctggggacag cctgtttctt 53700 ttctttttct attgtcaaga tacagacctacaggtgcagc ttgttaaata cctctccctt 53760 ccttcataat gcccagaaac cctcagttccccaccgcccc ctaaacatcc aaatcccttg 53820 gttacagccc tctctgttct cttacccattcccagagctc cactcaggag caagagctgg 53880 gagctgagac tggctgtgta gattcaaagcccagctctgt gtgaccttag gcaagtacct 53940 ctctgcccag cgcctcagtt tctctgtctgtaaaatgaag ggatggggtc tagggttcct 54000 ggccacatta tattctgggg aatcttcatctcccattgtc tgcatttatg agcccaacat 54060 ttgctagaat tccatctagc cccgttgaatagtccatcct caccaagtgt gaatctagca 54120 ttcagagcaa gtccaggatt ctaagttgatcctggtgtca catctctctg tgcccaggtt 54180 gtgccctctt acatcctcca ctttctcccctacctgaaag gacaggcaag caggtatccc 54240 atttatgtcc ggcaggtggg aggggtggggagtcacggag tcctgtagag acctatcctc 54300 cttccccatc tattctctct gatgtcccctgtctccagaa gacaggataa agtgtccttc 54360 accaaggagg gcagaagaat gtctatacttgccccaggat ggccctaggt agggtaacag 54420 ggcgcaggga ggccctgcct ctggagacgcacttctgttt ctgtcccgta tccttctcag 54480 ttcagagtac ctaaaactcc atctccacctcccttctcaa actcagttct ttgaggtggc 54540 attttaggca ccctccttgg ctccaagtgtcacactgtgt gccggcttcc ccccaactat 54600 cacaccgcct ccagtactaa caacttagccatcccagatg tcacagtttt agtcttcagc 54660 gacaagcccc ctcattttgc attggctcagagaggaaaag caacttggcc aaggtcacac 54720 agcaaaggtg gagcacagct gggtcctctgatacccagtc caggactctc ccaagggctc 54780 ctggagatgg ctaacttcat ctgtctccgggcatcctgtc actgcccctc agcccccagg 54840 gtgctctctt cacctagccc ctgctcgctgagcagaggaa agtaccagcc cctcagtcag 54900 gagcaccagg gagcctgcag tgtatgtggggggggtgtgt ggaaccaggg atcaggaaag 54960 cggggggcac tgggtctcag gggtcttaccttggagggtg ccccagtttg ggcaacaccc 55020 tggggcatgg gcagggaacc caggccagcccgggtccctg gcctcctgct gcccctgctg 55080 ctctggccct ccatgtctgc agcccccggcagcctggact cccttggctc cggctccagc 55140 tctaccgctc ccgggaacca gtgatgtcatcagccatttc aacctgctga gaatttaaag 55200 gcacaggctc ccacttccca gcctggaagaggccgaagca aggtggctac cccctgggaa 55260 tccttcaaac tggctgctga ggctggaacagccatggagt ggggagggga gagtgtaccc 55320 atctgcctgg cccaggtccc aactggcagcaggaaggagg ctgtctgtct accttcacct 55380 ttctgccgta ggcctggtca gccctttgctccagggaggg gcattaacac acctgcctta 55440 aggtaggaca ggtggttcag aggtctgcaccctctccagg gcctcagaga caactgagtt 55500 cttgccctga tcctgtgacc ttcctggctccctgccagct cagagcttgc cccggccccc 55560 acccttgccc cattttcagg tcttggtgccaccctctcca ctcctactgc cagtcccagg 55620 ctctattctt cccaacccag aaccagacactcaggctcca gccactgcag tcttttccca 55680 tctcaggcct cagcaccagc ccctcctcttctgcagacac ctagctgccc tcagatgtcc 55740 ccacagccag gcctaaccca gcccggcttctgtcagcttt cttctctcca gtattcactg 55800 ggtgtggttt gggaggggaa cttgctcaaggtcacctggt gaactgagaa ggtctcctgt 55860 gtttcagtga gaaaacttag tgacctaggatgagcacaag cccttcgagc tatctggggg 55920 aagggaactt gggtggagaa gggcccagcagtggggtaac agactgacaa gagagttaca 55980 aacaggcctg agaattgcta cagccaggacccagcccagg acatggtccc caacaggcct 56040 acgggagtgt ttgttgaatg aataaatgaattagaagagt gaatgggtga tgagggtcag 56100 attgggctgg gatggctgtg ggatctgtttctcatggctt agagaggagt gatcccaccc 56160 actttaggca gaaagtgttc agagttgtgtgtgcagagct ccctgttaac caacatggag 56220 catctgcatg ggcctgtgca gtctcctacatgaaggcaga tgcctcactt tcctctcctg 56280 aaggcacttc ctacctctgc ttgactgtcagtaggtctag tctgtattct caggccagca 56340 tctctgctgg aatttgcagg ggcagagactcaggccatat tagagtgttg gggtagaaag 56400 gtctttggac agcgatagtg gagatggtgacagtggtgac ggggaaggcg actgtggtga 56460 tggatgtgat gatgtatgta actgtgatgatggaagtagg gggctagcag tggttgtggt 56520 gaaggtggtg gaggtgatgg tgatggcaaaggtagaggtg atgatgatac caatactgat 56580 gatggtgttg tgtcaatgaa agaggtagtgttggagttgg aggtgacagt cagggaggat 56640 gtgagagtag acctggtggt gatgctcaggttaccagaaa aaggaagatt cgaactcatc 56700 ctgtcttatc ctctgtctcc tgttttacaaataagaaaat gggagccccc gggctggggg 56760 agtactggca aagtgcgggt aatcccagcactttgggagg ctgaggtggg cagatcacct 56820 gaggtcagga gttcgagacc agcctggtcaacatggcgaa accccatctc cactaaaaat 56880 ataaaaatga gccgggtgtg gtggtacatgcctgtagtct cagcgacttg ggaggctgag 56940 acaggagaat tgtttgaacc tgggaggtggaggtggaggt tgcaatgagc caagatcgta 57000 ccactgcact ccagcctggg tgacagagagaggccctgtc tcaaaaaaaa aaaaaaaaag 57060 aaagaaagaa aagaaaaaag aaaaagaaaatgggagcccc caagactacc cagcttttca 57120 tgcaatccta gagggaatga tgggcagatccaggcctctg ggaccagtcc taaggctcag 57180 ccatctaggg ctgggacagg ggcatcagtgccctttggaa gccaggcaaa tgtcatgcaa 57240 atgtgtctgc agagggctcc tctgcctcaggagggcaacc caggatttcc caccacccgc 57300 tccctgagct cagaccctgc aggggactttgtttctggcc ctgccactga cttacttgag 57360 gaggtcactc tgattcccaa tttgtgtaagggagattaaa acagcagaca cctcctaagt 57420 ttgctggtga agattcaaca ggataatatatatgaaatgt ttagcataga gcctgcctgg 57480 cacagcaagc tctccataaa ggtggctgctctgtatttat catcatcatc atcaccacca 57540 ttgacttcag cctgcccatg tggtggatgctgaaacaggc tgagggtggt tactctcctg 57600 ggaggacaag gaaggggctc tgagacccaagcctggtctt gtcaggagaa gggggtaggg 57660 ggcggacccc agctgaaaag ggagtgagttggagctatat ttgagctcct ggtgtgatga 57720 ctaaggaggt tgataacagg ctctggggctcagggcggca ggctgggggc agctgtcagg 57780 gagaaccgcc cccctggaga cggctgtctctggaggccct ttctggctcc ctccttgccc 57840 tcactcttgg tgggggaggg gggtgggcgtactgaggcag ggtccagggc tcatccagcc 57900 cactcctgga aactcagtgc tgtccttcaggctgtgtggg tcagggatag gaaggcagga 57960 tgccagtgat agatggagta tcccagttactctccatagt aaccctgtga ggttggtaat 58020 gaggccccca ttggacagag gaagaaaccgaggcccaggg attacacagc cagtagagag 58080 aggacagagc atggagctcc tggagaggcagtggataatt cttcccgaca gaggagctga 58140 ctgttgaacc ccttctttga aggagagtccgtgctgccaa atcgaagaag agaaacgccc 58200 tggctggaaa gcagagagaa cagcaggtacaaagcatgga tggggaagga aggttctggc 58260 tgtgaaagga tgagaaattt ggacatgtaccctcctgccc tttggttcgg agtaaacatg 58320 agcagggaag ggagagaagt ctttcctgtctttttcctcc tcctcttcct cggttcactt 58380 tccaggggca cctgaggatg gcaacggtaccgagggtctg tcctccttcc tttctctccc 58440 tggtcaccct gacccaggcc cgccatgagggaggtcatgc tatggctacc atctgcaaag 58500 gtgtagaggg tgatacagga tattgtgggaatgtgaaaga aggggttatc tgggagggct 58560 tccctgagga ggaagtatac agggcacaaaagagcatttc ttctcccaag gcttcactcc 58620 agggtttctt gttggtaaca agcttcacatgttatgtccc cagcacttca ttctcaccct 58680 ctgaggcaga tgtcatcctc actccccattctgccactca ggaaatgggc tggaggagga 58740 ggagtgactt tcccaaggtc acacagctggggctgagctc aggcctctct cctccttctc 58800 ttcggctccc cctcctccta ggcagcccagcacccgctgt cagctgctct gaagtgagtg 58860 gctattttta ttctggtgcg aggggatctcaagcagcaga gccatgtagg ttagaggctc 58920 taggacaccc ggcctcagca gtccaggggaaacttcctgc agccaccaga ccctgctaag 58980 cttgcctggg ggctctcatt tcttgcagactgacttgctc tgggctccta tgcctccaga 59040 agcttcttta ttggagctca gaacagagcatagagccaga ttaagccctg gtcatggtcc 59100 tgatcctcca acttgaaccc gactcttggtattgactaag cctctactcc agctcttgac 59160 tgagctctga catcacctta gaatgaaccctgactctagt cacatactga tctaagcctg 59220 aattaggctg atcccaactt gagaccttagttctgggccc agatcaagcc cttatccttc 59280 tctaagactg agccttagtc acagactgaattctagcccc agcccagact aaccttttag 59340 actgactctg gcagaagagt cagactaaccttttaaccct gactctggca gaagactgag 59400 ccctaatctt ggtcaaagac tgagtcctgagcctaatcat tgactgaact ctgaccacag 59460 actgaattct gaccctggat catgcaattctggtcacaca ctgagcccta aacggaagac 59520 tgtgccctga atctggtcac agactgagccctgaacttag tcattgacag agacatgacc 59580 ctggtcacag actgagcctg gctcctggtcacagactaaa gactaagccc aatcatggac 59640 tgagccctgt atctagccct aggctacagactactcaact aagggctgac ctagaccctg 59700 tctgagcctg accccatcac agactaatccccaaccttgg ccccacttga ggaagactgc 59760 tggcctaaat tacatgctgc cacataagaggcatggatta tgggcagaga tctgtcttgg 59820 gagatcttgg gcttctcatg ctgctgatgccacagtgttc cttcctggta ctgttatggt 59880 cacagtctcc accactggtt ccactggctggttggtcaac cctcagcagc ccaagctgtg 59940 gcctttaggg gccacagcat ccaggctaatgcaatgagag tggtttggtg gcatctgtcc 60000 agcaaacaac cagggcccat ggggtactggggtttggctc tgtcagcagc aagaacgact 60060 ccgtggggcc tctggcttca gttactctgaggcccttgct ggggtagggg ttggagtaga 60120 aggaaatagt ggggtatgtc ccattattttcgtaaataaa gtttactgtt tgtgtttagg 60180 taatccatgc ccattacaca aaacacagaaggaaaacatt tacctataat ttcatccacc 60240 aagaaataat cgttctgact tattggtttgtttccttata gatatttttt ggtgggggcg 60300 ggggtctagg catatatatt tatatatacatgttgtatat aatatgcata tatatttata 60360 tacatgttgt atataatatg catatatatttatatacatg tatatttaca tatacgtgtt 60420 atatatttta tatagctata tctattttttgagatggagt ctcactctgt cgtccaggct 60480 ggagtgcagt ggcatgatct cagctcactgaaacctccac ctctggtcca agcaattctc 60540 ctgcctcagc ctcccgagta gctgggattacagacatgca ccaccatgcc cagctaattt 60600 tgtattttta gtagagacag ggttttgccttgttgaccag gctggtcttg aactcctgga 60660 ctcaagtgat ccacatgcct tggcctcccaagtgctggga ttacaggcgt gagccaccaa 60720 gactgggcct atacatgttt tatagaattggttggttact gtgttgctgc cacaatgtcc 60780 agcaacacag tagggttagg gttagggttaggatcctgtt aaggttgcag cccatctcct 60840 tcttaacagg aactggaata tggtggaccccaccctcagc ttcaggaatg ggtcccagtt 60900 ggttaagcca gtaagcaatt cccatttccccaggcacatg attagatcac gaatgaacta 60960 gcaagataca aggaaatttt tgctcagggcttttgggaaa ggaagcttat tttctctcct 61020 gaggaggctg ccaaaaaaga tgatcttccttccattagat gtaaatgaag aggccaatgg 61080 ctctagttac tgctggcagc catctttacaccatgtagaa aattggccta ctgataaact 61140 gacattatgg aaagcagaat ggagagacaccaggctttgg tgacttcatt aactggatca 61200 aacttcacct gaagccccac ctgccattggactttttttt tcttcttttt gaaatggagt 61260 ctcaatctgt cgcccaggct ggagtacagtggcacgatct tggctcactg caacctccgc 61320 cacccaggtt caagcgattc tcctgcctcagcctcccgag tagctggagt tacaggtgcc 61380 caccgctgcg tttggctaat ttttgtatttttagtagaga cggggtttcg ccatgttggc 61440 caggctggtt tcaaactcct gaccttaggtgatctgcccg cctcagcctc ccaaattgct 61500 gggattacag gcgtcagcca ctgtgcctgtcctggacttt taaaattatt tgagccaaca 61560 gagtcccttt atttatttat ttatttagagactgagtgtc gctctggcac ccaggctgga 61620 gtgcagtggc gcaatcttgg ctcactgaaacttccacctc ccgggctcaa gcaattctct 61680 tcctcagcct cctaagtagt tgggattacaggtgtgcacc atcatgccca gctagttttt 61740 gtgtttttag tagagagggg gtttcaccatgatggccagg ctggtctcca tctcctgacc 61800 tcaagtgatc tgcctatctc ggcctcccaaagtgctggga ttacaggcat gagccactgg 61860 gcccagcccc tttattttta ttattttttgacacagggtc ttactcacat tgcccaggct 61920 agagtgcagt ggtacgatct tggctcactgtattattttt tattttttat aggagatggg 61980 gtctcactct gtctcccagg ttagagtgcagtggcatgat catagctcac tgtagtcttg 62040 aactcctggg ctcaagcagt cctcccacctcagcctctgg ggtagctggg actacaggca 62100 ctgccatgcc tggctagatt ttaaatatctttttttagag atgggttctc actatgttgt 62160 ccaggatagt ttggaactct tggcctcaagttatcctcct gcctcagcct cctgagtagc 62220 tgggtttata gacacaagcc accacaaccagctcccttta ttgtttaagc cagtttaaat 62280 tggggtttct atgacttgca gcccacagcatcacaactcc caattgatat taccagatta 62340 ctgtttttgt tgcttttttc ttgctatttaataccataac cacgaacatt ctccatgtca 62400 ttccatctat gctgcatctt tttttttttttttgagatag agtctcactc gcccaggctg 62460 gagtgcagtg gtgcgatctc agctcactgcaacctctgcc tcctgggttc aggcaattct 62520 cttgccttag cctcccaagt agctgagattacaggcagcc atcaccatgc ccagctaatt 62580 tttatatttt tagtagagat ggggcttcaccatattggcc aggctgctct caaactcctg 62640 acctcaggtg atccgcccac ctcggcctcccaaagtgccg ggattacagg cgtgagccac 62700 ccacgcccag cctgctgcat catttttaacaattgcatgg ttttccatcc tatggaggta 62760 cactcattaa tttaactcat cccctgctgtgacatgctta ggttatatcc ccagttcttc 62820 accacgataa atggtattct aataaacaagcttgacctaa caatcctctc tctgatgatt 62880 actttggggc taattctgaa aaatggaattactgggtcaa aaaaagtttt tagagttttg 62940 attttgccct tcagaaagcc agggtgaattcatacttccc cagcagtgaa cagagtgtta 63000 gagatagctt actgtgtgaa tagtctggacaagactaatc atattgacta catactcata 63060 ttatatatat atatatatat atatatatatatatatatat atatatatat tttttttttt 63120 tttttttttt tttttttttt ttttgagacggagtcttgct ctatcaccca ggctggagtg 63180 cagtggcaca atcttggctc actgcagcctctgcctcccg ggttcaagtg attctcctgc 63240 ttcagcctcc caagtagctg ggattataggcatgcaccac catgcctggc taatttttgt 63300 atttttagta gagacgaggt ttcaccatgttggccaggtg gcctcgaact tctgactcaa 63360 gtgatctccc tgcctcagcc tcccaaagtgctgggattat tggtatgagc caccatgccc 63420 ggccaagcct attattttta tatctttacaatcaagttag taaaggggaa gttagcaggg 63480 tgcaaacaaa agactcagtg cagacttaacttctctagaa ggcacagtag gctcagtgtt 63540 tagggcccac tatactttta gggggtccatgaaagtgttt tttttttttt ttgagacgga 63600 gtctcgctct gtcacccatg ctggatggagtgcagtggcg tgatctcggc tcactgcaag 63660 ctccgcctcc cgggttcacg ccattctcctgcctcagcct cccgagtagc tgggactaca 63720 ggtgcccgcc accacgcctg gctaatttttcgtattttta gtagagacgg gggggtttca 63780 ctgtgttagc caggatggtc tcaatctcctgaccttgtca tccgcccgcc tcggtctccc 63840 aaagtgctgg gattacaggc gtgagccaccgcgcctggtc gaaaatgttt ttaatattct 63900 ttaaaattag aaggatacac tgggaagttaaggttaaaaa aaaaaggaaa catatactaa 63960 taataatgaa tccagcctag attatagttatctttttacc aaagcaattg aaaatcaaat 64020 atatataata tttatgtata ttatgtatatttaatggagg catgtgtcca tatcccagct 64080 actcaggagg ctaaggcagg agcattgtttgaggccagga gttgaacact agctgggaca 64140 acacagaaag accctgtctc taaaaaaaaaaagaaaaaag aggccaggca cagtggctca 64200 tgcctgtaac cccagcattt tgggaggcggaggcgggcgg atcacttgag gttgagacca 64260 gcctaacatg gtgaaatcct gtctctactaaaaataaaaa aaattatccg ggcatgatgg 64320 cacgctcctg taatcccagc tacacaggaggctgagacac gagaatcgat tgaacctagg 64380 aggtggagat tgcagtgagc caagattgtgccactgcact ccagcctggg cgacagagca 64440 agactccgtc tcaaaataaa aataaaaattaaaaaaagaa aaaagaaaga aaaccctagg 64500 atccatgaaa gtcataatgc agccttggctcggtattgag aaggagtccc tagattcaat 64560 gggaaaagag gacagtgacg aacttgctgtgtctgtggaa gaaagcatga agaagagaac 64620 tggcatccta atctggtgat ctggtgatccgttctccttt tttttttttt ttttaattgt 64680 aggcatttta tctgcaaatg catattacctccttagaaaa agaattccag gattttacct 64740 cctgtgtgtt ttcgtcttgc ttctttgtgatccatgatgc cagctgaggt tgtgagtaca 64800 atgaaaccca actggcagga tgggagcagattattctgcc atttttctag atttttgagt 64860 tgcacatcaa atcaggggct gattactccacacttgttta acctgcctgt gaggttcaca 64920 gcagttttcc tagctctgtg atcatcaatgacttcaactt caccagtgta actatgcttc 64980 atcaccacag ttagaaacca gacgacgacattataagaac ctggtgtttg cctctctttt 65040 ggcattgttg atgctcttga gagcatcagccgggacattc atgcacacca ttatggcagc 65100 acatggcaga aagagctatc tgcttatgtatgagattgag aggtgaagcc agctggactt 65160 cctgggtgga gtggggactt ggagaaattttctgtctagc cagaggatta taaatgcacc 65220 aatcagcgct ctgtgtctag ctgaagaattgtaaatgcac caatcagcac tctgtaaaaa 65280 tgcaccaatc agtgctctgt gtctagatagaggattgtaa atgcaccaat cagcactctg 65340 taaaatggac caatcagcac tctgtaaaatggaccaatca gcaggatgtg ggcggggaca 65400 aataagggac taaaagctgg ccgccactgccacccttcat ccccagccag cagccggcaa 65460 cctgcttggg tgcccttcgg tgctgtggaagctttgtcct ttcgctcttc ccaataaatc 65520 ttgctgctgc tcactctttg ggtcctcaccacctttaaga gctgcaacag cctgtaatcc 65580 cagcaccttg ggaggccaag gtgggcggattacgaggtca ggagatcaag accaccctgg 65640 ctaacacggt gaaaccccat ctctactaaaaatacaaaaa attagttggg catggtggtg 65700 ggcatctgta gtcccagtta ctcgggaggctgaggcaaga gaatggcgtg aacccaggag 65760 gcagagcttg cagtgacctg agattgtgccactgcacttc aacctggggg cgacagagcg 65820 agactccgtc tcaaaaaaaa aaaaaaaaaaaaagaaagaa agaaaagaaa aatagaaaaa 65880 agagagttgt atcactcacc gtgaaagtccgtggcttcat tcttgaagtc agtgagacca 65940 ctaacccact ggaaggaaga aactccagacacatttgaag gaacaaactc tggacacacc 66000 atccttaaga gctgtaacac tcacagtgaaggtccgcggc ttcattcttg aagtcagtga 66060 gaccaccaac ccactggaag gaagaaactccggactctca agatgagtgc agagacatgt 66120 tgggttcaag tcccaaatcc acagttcactcatttcacct ttctgagcct gtttcctaac 66180 ctgcaaaatg gagttcacgg ggtctttatgaggtaaggaa ggaactgata atgaaagcta 66240 acactgtcct agtaggtact tttttttttttttttttttg agtcagagtc tcattctgtc 66300 gcctggctgg agtgcagtgg cgcgatctcgggtcactgca acctccgcct cccaggttca 66360 agtgattctc ctgcgtcagc ctcccgagtagctaggatta caggcatgca ccaccacacc 66420 tgggtaattt ttttgtattt ttagtagagacggggtttca ccatgttggc caggatggtc 66480 ttgatctctt gacttcgtga tctgcccgcctcagtctttt tttttttttt ttttttttga 66540 gacagtctca ctgtgtcgcc caggccggagtgcagtggtg cgatctcggc tcactgcaac 66600 ctccacctcc cgggttgaag cgattctcctgcctcagcct ctggagtaac tgggactaca 66660 ggtgcccgcc actatgtgcc cagctaaatttttttttttt tttttgagac agaattttgc 66720 tcttgttccc caggctggag tgcagtggcgccatcttggt tcactgcaac ctccgcctcc 66780 gggttcaagc aaattttcct gcttcagcctcccgagtagc tgggattaca gacatgagaa 66840 tcatgcctgg ctaagttttg tatttttagtagaggtgggg ggtttcacca tgttggtcag 66900 gctggtctcg aactcctgac ctcaggtgatccacccacct tggcctccca aagtgctggg 66960 attacaggca tgagccacca tgcccgtcctgtattaggta ctgttctaat gagctttata 67020 tgtgttaacc cctttatcct gccaatcccaacagggtaca caatattgca tcaccacaat 67080 gtgtgctctg ggaagtaaaa accttgattggaatttttgt ccaaagaaat aaaaaggcca 67140 ggtggagtgg ctcacacctg taattctagcactttgggag gctgaggcag gaggatcact 67200 tgagaccagg agtttgagac cagcctggtcagcagcaaga ccccgtaatc tactgaataa 67260 acaaacagcg caaacaggga ttccctagggttcggttttc ctatctcttt ttttctacaa 67320 ccaaattggt ttattacagg aatgcaaggtttaacatatg aaaatcagtt cacatatttt 67380 accacattta ataaaataaa ggagaaaaaccacatgatca tctcaataga tgcaggaaaa 67440 catttgacaa agttcaacat ccattcatgataaaagctct aagaaaaata gaaatagaaa 67500 actttctttt acaaaaggca ccagtaacaaacctacagca aacatgatcg tttaaagatg 67560 atatctggaa aaagacaatt atcagttccagtcaacattg taccagaggc cccagaccgt 67620 aaaattaaga cagtgcaacg aaacaaaaccaaggtataag gaccagaaag gaagaaaacc 67680 acttttattt ccagatgata taatatgcatatgtagaaaa taaaaaaaaa tatccagtta 67740 aactattaga gtaagaaaat tcagtaaggtcactggctgc aaggttaata tacaaaaatc 67800 aattgtcttc ctatatgcta ctaccaagcaacttgaaaat gaatatgtaa aaacaataga 67860 gtttgtaatg ctataaaaaa ttaaatacctaggagtaaat ctaatgaaag atatgcaaga 67920 tatttattct aaaaaccaca aaatattattgaaggaaatt aaagaagacc tatagaaatg 67980 gagggactta ctatgttcgt ggaagaaaagtcacaataat gtaaagctgt agagtctccc 68040 cacattgatt tccccagtgg gaatctgaaatcctgataga aatttggaag gtttttctgt 68100 ggaggttgac gagctggccc taaattgtacctggaagtgt gaaaggccaa gtatagtcaa 68160 gacaaccttc aagaagaaca aagctagactgcgatggctt actgaggctg tgggatcaca 68220 catggccctc accacaggaa aatgtaggccacaggccagg catggtcgct catgcctgta 68280 atcccagtac tttgggaggc caaggcaggaggatcacttg agcccaggag tttgcgacca 68340 gcttggtcaa catggtgaaa cctcgtctctactaaaaaga caaaaaatta gccgggtgtg 68400 gtggccgacg cctgtaatcc cagctacttaggaggctgag gcaagagaat cgcttgaacc 68460 tgggaggcag aggttgcagt gagtccggatcatgccactg gacatgagag tgtccagcct 68520 ggacaatgag agtgaaactc cgtctcaaaaaaaaaaaaaa aaaatcagct gggcatgatg 68580 gtgcatgcct gtagtcccag ctactcaggaggctgaggtg ggaggattgc ttgagcctgg 68640 gaggttcagg ctgtgattga gccactgcactccagcctgg gcaacagagc aagactctgt 68700 ctcaaaaaaa aaaaaaaaat agccagcccagcagctcaca cctgtaatcc caggactttg 68760 ggaggccaag gcgggtggat gacttgaggttaggagttcg agaccagcct ggccaagatg 68820 atgaaacccc catatttact aaaaatacaaaattagctgg gcgtggtggt gggcacctgt 68880 aatcccagct acttgggagg ctgaggcagaagaatcgctt gaacctggga ggtggaggtt 68940 gcagtgagct gagatcgtgc cactgcactccagcctggct gacagagcaa gactctgtct 69000 caaaaaaaca aacaaacaaa aaaacaaaaaaaaatgggcc aggcgcagtg gctcacacct 69060 gttatcccag cactttggga ggctgagacgggcggatcat gagatcagga gatcaagaac 69120 atcctggcta acacagtgaa accccatctctactaaaaat acaaaaaaat tagctgggcg 69180 tggtggcgcg tgcctgtagt cccagctactcgggaggctg aggcaggaga attgcttgaa 69240 cccgggaggc ggaggttgca gtgagccgagatcaggccac tgaactccag cctgggcaac 69300 agagcgagac tccgtctcaa aaaaaaaaagaaagaaagaa agaacaaagc tagaggacca 69360 acacacaacc agatgtcaag tctgactataaagctatagt taataagaca gcgtagttag 69420 acaaacccac tgaaggacta gaatagggtatgatattcag aagtagactc ccatatattt 69480 atatggttac ctatttattt atttatttatttttgagaca gtctctgtcg cccaggctgg 69540 agtgcagtgg taggatgtcg gctcattgcaaactctgcct cccaggttga agtgattctc 69600 ctgcctcagc ctcccaagta gctaggattacaggcgccca caccacgccc agctaatttt 69660 tgtattttta gtagcgatgg ggtttcaccatgttggccag gctggcctcg aacttctgac 69720 ctcaagtgat ctacccacct cggcctcccaaagtgctggg attacaggtg tgagccacca 69780 cgcccggccg tggttgccta tttatatataacagaggtaa cgcggcagag tagcaatgaa 69840 aaagacaaga tttttaattg aattggatagccacattaaa aaaaaaagta aatcctgact 69900 ccataaattt aacccagctg atttaagaccctgttgtggc ctatcagctg taaccctcct 69960 tgcattttcc cacctttgaa tagcaaattcctttcctcac cccaggtcag aaagtctgct 70020 cagcagtagc tgtggatggt aagaagacacgctggtaggt ctcagtggct cccagaagcc 70080 gcaccccctc caccgaacct cactcctcatctcccacgct ccaaagcgag gagtcctcag 70140 aaagccagtt tcccttattt attcttctttctttctttcc tttttttttc ttggatgtcc 70200 taccagtttc cctatcttaa agtcgcaggttcggctcaga aactccagtg tccctcagcg 70260 tctcgccggc accctctgcc ggcgtgaggtggcgctgcct ggccgcatcc tgggggagcg 70320 tccacatcct cggtcgacaa aaggagcgtcgacactctcg gacctgggaa agtgacggcc 70380 caaacgccag ggaggagcca ggacctcgccctgagctagc gggaggtaac ggcggggagt 70440 cctggggcgg agaccgagcg ctgggggcgtggtctccagc gggactgggc ctctagcggg 70500 agtgggggcg ggggcggggg cggggccagcctgggggccc agacgtggcg cagcgactcg 70560 gaggttcgcc tccagcttgc gcatcatctgcggccgggtc ccgatgagcc tcctgttgcc 70620 tccgctggcg ctgctgctgc ttctcgcggcgcttgtggcc ccagccacag ccgccactgc 70680 ctaccggccg gactggaacc gtctgagcggcctaacccgc gcccgggtag aggtgagtac 70740 gccggcctcc agccccggca ctatcgttccccaaccctgc ggccccatgg gagcaccgtc 70800 cgtcccggcc ccaagaccac ctcgaaccgcgagtctccct gctttccccc tggcgccggg 70860 accatccctc ctgttcccta gccccagatggccccagcat ccaccgtgga agcctgagac 70920 accgactttg gggcctggaa ctccgaacccttccccagct ccccctaccc ggtccgacag 70980 cggacaccca gacacactga cgcagtctcctaactcttct cgtggcctat gactcccaat 71040 cctgtcccaa cttcccatcc cccatcacttcatgttttcc tggaattccc ccccgacccg 71100 gttccagggc tggaggctcc agaaagtctcttttccttct cctgggggga aagaagactt 71160 tctgggtgcc tcctcccata tgcaggatccggggaagggg gccaactcgg aggggcaacc 71220 gagttgggaa cttggttgcc aacatttactctgcagcagc ctcccatcct cccccaacca 71280 ggaaattccc gttcggagtc cctgtcttgctatgtgactt tgaccatcac agcccgcctc 71340 tgagcttttt gtcagctctg tctgacaaaagggtgtagaa tggttgggtg ccggtggtgc 71400 acgcctgtaa tcccagcact ttgggaggccaaggcaggag gattgcttga gcccaggagt 71460 tcaagaccag cttgggggac atagtgagaccctgtctcta agaaaagggc tgagggtagg 71520 atggaggagg gctggagtgg gtggtcctggggtctagact cctgctggat ggtggcatct 71580 cctcagggaa ggcagggagg agccctcccatcctcccatg tcagggaagc aaccacatgg 71640 tctgtggggc tgggccgcag gtggcaggcagggtgaggtc tgcctgtgta gagtagggac 71700 cagatggtag gtgtctccaa tgggggcccccagggccatt ctgaggtgtt tccttctgct 71760 ctgcctccac tgtgagattt cagggatcaaaggccaagcc caggtctcta ctgcttaaga 71820 ggagcagggt gatcatttcc cctgggcattgggagtcagt ccacagccag taggatgtac 71880 aggccccaag gctggcaggc acactgtgggtctctggcct tgctcttttc ccctggtgtc 71940 tctaggcctg agtctcccca cctgtatacacagttccccc ttctgcccac aagggtccag 72000 catttccttc agaccttggg aactgctgatccggggataa ctcacagccc gacccaactc 72060 agggataagg aagtatggct ttggggatgtgactggaata aacgtgaagg actcctgacc 72120 tatcccattt tatccccctc cagacctgcgggggatgaca gctgaaccgc ctaaaggagg 72180 tgagtttgaa ggaagaggtc cctagctctgttccccctga gcctcttggg gagtgggcaa 72240 catggtccca atgactgggg cggggaggggggaaggatcc ctaggctgag agtctagcct 72300 aggctgagag tctagcctgc acctgacttgctttatgacc tcactgggct tcagtgtctc 72360 gtctgtacct cgagtagact gaggtcatggtctctgatgc tctggttcct ccccaggtga 72420 aggctttcgt cacgcaggac attccattctagtatccttc tgttctgggg gaggggaaat 72480 gggatgggca cctgggagaa tctccacgtaacttcagaaa ggggtggcag atggttttca 72540 actgacaagt tgaattgatt ggtagtggctcccagaggat tctgaggtgg tctccatgtt 72600 gggtgggcaa gagagattga ctagtgatgactgccacaga atggagagga gggcccttta 72660 cttctttgaa ccctaatttt ctcacgtataagcggagacc ctggcccctc ccgggcacag 72720 agtaagctct gagcaaagga ggcaatgctgttcccatcag taaggctgcg gaaaccacca 72780 cctccctctg cccaccaccc cgctccttaacaccacctcc agtcacaacc tggtgatgaa 72840 acacctccct ggggccgacc ctgagctcgtgctgctgggc cgccgctacg aggaactaga 72900 ggtgaggccg tgggaggtgg gctgggggcgaggccagagg cgaggcccag cctgctgacc 72960 ccgcccctcc tccgcctcag cgcatcccactcagtgaaat gacccgcgaa gagatcaatg 73020 cgctagtgca ggagctcggc ttctaccgcaaggcggcgcc cgacgcgcag gtgccccccg 73080 agtacgtgtg ggcgcccgcg aagcccccagaggaaacttc ggaccacgct gacctgtagg 73140 tccgggggcg cggcggagct gggacctacctgcctgagtc ctggagacag aatgaagcgc 73200 tcagcatccc gggaatactt ctcttgctgagagccgatgc ccgtccccgg gccagcaggg 73260 atggggttgg ggaggttctc ccaaccccactttcttcctt ccccagctcc actaaattcc 73320 ctcctgcctt aactgaggct cgactccttcgttgctgcgg gcgggtgggg tgggaggtcg 73380 gaagaagaac ctctgaggat ccctgctggagttggagacc ttgcggagct gccttcggtt 73440 caaaccccct ccccaccccc aggagacgcagagaggagtc aggatcgttg aaaaccaata 73500 atttatcaaa acgctgcgtg tgtatgtgggggggagggtg tcgcaacaga cagggcagcg 73560 gtgggcggac gcacaggcag gagacggtgcccggagagtg ggggcggcag cttgccactg 73620 gctggccatg cgggcgggca ggctagacattcttgccgcg caggcgcagt tcgtggcgtc 73680 gcaggtggtt gtagagcgac tgcacataggtgaagacaca cttggggtca ggcttcttgc 73740 ccatgatcat catgtcgtcc acctccaccaggggcacaca gtccaccagc atcctgcagg 73800 gagggggcac ggggttggat gtcagcgccagacccgcctc tcgtggcgcc cctctacccc 73860 aaggtctttt ttattgccgc attgcctgctggtctttcat aaactccaga cagggaaaag 73920 ccttccagga aggcaggaag cccctggcttcatctaccca agcctggagg catctctcgg 73980 ggcgggggag cagagctagg caggtggaggcggagatggc agaagagagc cccatcccag 74040 tcaggcaggt cctgggtctg cttcctccaaccctggggag gtgctggctc caaaccctgc 74100 ccatgttctc cctggagacc accttctgctcaccctcact ggcacactcc agttggtaga 74160 agcctctcag ctcggccttt gcacccagatgggcttcatc actggccaat ctttatctat 74220 ggataggtct cactctagtg gccctgtggtccaccgatga ttgtctgcta gctgcctgat 74280 ctggtacttc ctgttgagag gcccagggacccctattctt tgacaggggg tggggataac 74340 cctgctgctg gagatggagg ccagggaacgtgtgggcagc agaggggttc tctaaccctt 74400 atcacctgcc ttgggtagag cagaggaggcagatgaggat cccagccaat accaatggac 74460 catctatgcc atgctcgggg ggaccacccttctggccatc cttcagaatg ctagctgccc 74520 ttcacagata aggaaactga gtcacagagcagaggagcca tttgtttcaa gccccatggc 74580 ttagtaagtg caggctaggc cgcatgggacccaggccccc agttctgggt gttggcaaag 74640 ccttttcccc actctggagt gagtgggttgtgcctattaa gcaactgaca gctcccagag 74700 ctctgaagct ggagtctgct ctctggctccttttcccctg tccctcaacc cccagagcaa 74760 gacctcttct gccttgatcc ctcctatctgccatacctgg gacatagcaa gcattcaatg 74820 ttgctgaatg agtttcctat ggcagggaaggcataatggc aacaattgct ccttattctc 74880 aagacacctg agaacccaag accacctcccatctcgtgcc cttatggaca aactcagaac 74940 tgtggtaggg ctgggcctac ccccagctcacctggactcc ttcagagaag aaacctggga 75000 ggcagaacac cgaacacctc tgttttagtccagactgtat ccctaaccag ttgtgggtgc 75060 tagataaggc ccttttctat gactgtttccccctctttag aacaggacag ttattctcta 75120 tctcatttga gaccttacaa gaatttaggatgagtgagag ggttctgggt ctgctgctga 75180 tgtgccacgt gcccctaggg tcatccctatcccagactgg gcttgtttcc cgagctgtac 75240 catgatgcaa aggcagcctc tctctgaagcttcttccagc tgtggctatc gtcctgggga 75300 tcccgaccgc cctctccaac ctggtgctccctcccgcccc actcccttcc ctggagacct 75360 tataaagcca ttgtttacac tggggctcagggctcagggc tcaggctgcc ccagtgacag 75420 gccaaacacc aggcaacttg agcaacagcacggctgagtc acactttcca actggatcag 75480 ggctgggctg ggcccctctc cctccaagctggcttgctgg gcagcagctc ctaagtccat 75540 atatgatctg gagatagcac caagcccatccgccactcat ctgtgctcct tctctgagtg 75600 tgtgtgtgca catgtggact gccccccacaatggctccag gccctgaggg gcatctgagt 75660 gtgcccctac ctgtcactga ctcacattccttcagccaat ccccttgctc cttctgggcc 75720 tctattttca atcctctcta caaaatgggcgggaacacag tgatggggca aggaaaacag 75780 ccactaagtg gggagtttgg agtctcagtttctggcccca gctctgacct aaccatcttc 75840 cctctccctc ccacccccag gacagtcttagcccacgtct ctctctgagc tccttgtctg 75900 taatggggta gttagtttag gatctgaattctttactttg gtactgaggt gaggtgacca 75960 gagaggaaat gccacagctg gcttaggatccagagtcccc agccagaaac atcttcctgt 76020 tgaactggtc ctgctcctga gctccccactttggagtatg gcaccaccaa ctccccagtg 76080 cccacacagg agcctggcag acttcttgaccttccctctc cctctccaaa ccagatctat 76140 tgggaagcct gtctctctag ctcttaagctattccagtca tctagtccat cccatctctc 76200 atccaagcct catccgagga aggtcctagaatgctatatc catcccttct ctgtttggaa 76260 accctttata actcctgttg tcctcaggaggaaggtcaaa cttttttttt tttttttttt 76320 tttttgagat ggagtctcgc tctgtcacccaggctggagt gcagtggcat gatttcagct 76380 cattgcaacc ttcgcctcct gggttcaagtgattctccta cctcagcctc ctgagtcgct 76440 aggattacag gtgtgcgcca cacgcctggctaatttttgt atttttagta gagatggggt 76500 ttcaccatgt tggtcaggct ggtctcgaactcatgacctc gtgatctgcc caccttggcc 76560 tcccaaagtg ctgggattac aggcatgagccaccgtgctc ggccagaagg tcaaacttct 76620 aactgtggcc ccctcctccc tcatatccagactcaagttt cttcccttcc tgatgtgctg 76680 tgctctccag ctctcttgcc ctgctaagcctaggctgatt cctctgcctg gaactccctc 76740 tccctccttt agcctgaact tgttcagatcccagcttagt ttgcactttt ttcagatggg 76800 gggcccagac ctgcagcctg ggtcaggcatctcccctggg cttcccccat cacagtgctg 76860 cccacctggg tcatcactgc ccatttagaatggtctcacc tgctgggccc tgaactgcca 76920 gaagacaggg ctatgtctgg ctcctctggcttgactaaat gcccccctta cttcccccac 76980 ccgcctccct ggaccctctc tggccttgctgagcagattc tggtgaaacg gggcaggtgg 77040 tagaggcggc gtttctcacc gtggggccccgagcaggggt taggactttt tggtttttac 77100 cagccccttc tggaccagac agcggtagaattcctggatg tacgtgtaca cgcacttcca 77160 gtcaggctct cgaagccgca ccatgtcctctgtatccagg agctgcgggc agtccgcatg 77220 ggtcctgggg agggtagggg gccgggaaggggtgggggac gggggcagga ggccagggcc 77280 ccgggtgggg aagagaggga agaggcagagaagagagagg ggaggaaaca gagacacaca 77340 cacatacaca cacacacaca gagacatgagttcaattacg attccagtgc tgcagtctgc 77400 cagccccccg catgcctcct ccccactgtggacgtgccgc tcactaccca tcactaatgg 77460 tgtgcaatgc agacaagggt gggggccaaaccagtcacag gtgcagagaa ctctaggggc 77520 aagcgggaac gcggggtggg ggcgatggcgttggcaccaa ggttggagag gagggctgtg 77580 ccccggggag agggggtgag ggaggcgtgagaggaggtgg ggggaggagg aagaggagaa 77640 ggaggaggag gaagaaattt gagggaaaccagaaagagaa ggggaaagaa gggaagacag 77700 atggagaagg gtgctgaggg tgaggtgagcagacggggca acgattccaa agtggagggc 77760 ttgctgaggt cctatataag cctctggcagcactatatag gctgggcggg cacggtgccc 77820 gggccaggag cctccttttg gaatctccagccgggatccc gtgggagcag gaagctctgg 77880 tgatagtggg aggagagcag gacagagaaagggagagaga gggagaaggg ggcagaggga 77940 ggatggaggg gatatggaca gggccacctggtgggctttg gcccgggctg gtaggccggc 78000 ctgcggctcc ttcgttccgg cgggcacctggcacgctcag cagcgggggg gtggggatgg 78060 agaaggacgg ggactctctg gggaagggggtctcagccgc tgactgacaa tgtggctggc 78120 ccgctccagg ggttctcagg gcaactgggcctggtcccga tgtccagccc cagatgtgca 78180 gcaacattag cagggccagg gcccacacttactccgcaga tgagaaggcc acctcgaagt 78240 tctggcgtcg gttctgaggg ctaagctgcccatagtcgaa ggcctcaggg aagaagttgt 78300 gcaccagggc acagaaggcc atcccatcactccagctgga ggagaagttc tggatgtcga 78360 cgtgctataa gccgtaggag gactggtcaggaacctgggg gcaactcccc cctgctgtct 78420 acccctcagc attctgttat tccagacctagggcactggg cacaaagagg ccccgtagct 78480 tgcacaatga gtgaatagtt ggaacatgagcctcctccaa gtcagcctgt caactcccat 78540 atttgcaatt tcaagggaca gagctactgagaggcccagc gccacccagc taaggctatg 78600 gtcatgcctc atcactcctt ccctcatttagagaaattga ctcagggcct cctacagagc 78660 aacaaggagg ggactccaag agtgggatccggccttgaac cctgcccacc acccaagagg 78720 ccctgttact tcatcactga ttctggaatctagggcttgc cttgtgtcct ctttgagcct 78780 cagtttcctc accccaagag cctttccatgttccctgtga ggccacacag tggcaggaag 78840 tgtactgggt aataggagct ctgctaagaaggaggtgttg agctggggtc tggggaggcc 78900 tccaggcccc ctggcctccc ggggctcacctcgtagccgc gagtcttggc tcgacaccag 78960 tccagcagca tctgcttgat gctgttggcgttggggaccc cgaagctggt ggatcgctgc 79020 acggctgcgc ggggtccgcc agggctgctgtaggggcggt gtcaggacca ggtcacacga 79080 ctataagggg catgcctcgg tgggcccacccagtggatcc caggccccgc cttccatgac 79140 cttcgggcct ttgcaccaca gatctagccgcgcggtcttc ccgcctctgc cgggccaact 79200 atcaagcccc gccccccact gcctatcacgccccgccccc cactgcccag cccacttctg 79260 cagctcaccc ggccgcgccc tccttctccagcttctcaat catggccttg cgcgcctggg 79320 aggctgaggt cttgggcaga ctctgcgccttcatcagctc tttcttcttc tcggcctgcc 79380 gtttctcgag cgccgccagg ctgccggcccgtgggctggc ctggtcctcg cggtcgaaga 79440 tgctaggggt tggggaggcg catgttaggcagggagagca gggctgctcc ccagcctgga 79500 ccaccactcg cgaggaggag ggggggtcttgtagcacact agtatctcca ctgccacaaa 79560 cgcctgccag ggagggaggc gtcctcatcacacgcatttt agaggagtac actgagtctc 79620 aaatgacagc aaggttttca acaggtttccgcctccccct cccccaccca cgagtagttc 79680 tctgagaagc ctcattgtac cctcaagttacaggggagtt cagcttctgg gcactatccg 79740 ataataaaaa tgatgactag cataataatagtaataataa taattcatct ctgttgatcc 79800 tttcctgtgt gccattttaa acttcacaagagcagggagg ggccttacca attccactaa 79860 aggtgaggaa actgagacct ctggcagtaacttgcctaag atttcagagg acgtgatggg 79920 cggaactaga acttgaacaa ggtctctctgattcagagtc tctggacccc tttggttctc 79980 atcctggatt ctgatcctgt tcctgctttctgccagcccc aacagcctct gttacatggg 80040 ggtaccctcc tttctcatgg ggctaaggtataaaggtgct gtgtgacctg ggacatggtt 80100 tgcagatact gggaagtggc agtgccaccaggcagctcag tgtggtaggt aggcctctgt 80160 aagtgttcaa tgctattgca gccactcagagatgtgagcc cctaagcaac tcactggcct 80220 ccctgagcat ccacctctcc tgtggtgtggttgagaataa aatgagatcc caaggagagc 80280 aggatcctta actctcactt tgcccctccctggctataga cctattacct cccagcatcc 80340 cagtctaccc ctctgtttta tttatttatttatttattta tttatttatt tatctattta 80400 tttttgagac tgagtctcgc tctgttgcccagactggagt gcagtggagt gatctcagct 80460 cactgcaacc tccgcctccc aggttcaagtgattcttgtg cctcggcctc cccagtagtt 80520 gggattacag gtgcctgcca ccacgcccggctaatttttg tatttttagt agagatgagg 80580 ttttaccatg ttggccaggc tggtcttgaactcctgacct caagtgatcc gcccacctcg 80640 gcctcccaaa gtgctgggat tacaggcaagagccactgtg cccagcccac ccctctgtaa 80700 aacgggtttg cagttaggtc ccctgtggcactgactcctc tatggtcagg gattgggtgc 80760 tggtgctcac ctgcccatct tcttggatgaggaggaagag gagaaggtct tggtttgcat 80820 catggtgctg ccactgccat ctgcaaaaaaggggaagggg caccaggtga gggcctgggc 80880 tggacatcag gagatgggat gggaggctgtatggaggggt ggtgatagcc gcaggcagag 80940 aagagaaagt gacggcacag ttgaagacacggagagagag ctcaaggaag agccggagga 81000 ggtgggcgga caggcaggca ggcacagggcgacaccaggt ggccttactc tccgagcgcc 81060 tcacgaaact cgactccact gtggtggtgcgggccgtccg tgtgccatca tctgcagggg 81120 caggggatga gaaggatgtg aaaggcacagggggctgggg gaggatgtgt tcccaccctg 81180 agccctgggc cggccccatt tggccccttactggagtgga cgagccgctc agtcttggta 81240 acagtgctga cagcagagcc atcagctgcccgctggctgt gcctcgtggt ggtctcagtg 81300 gctgtgttgc cgcgcccctc ccctggccggccccgtgcct cctgcagccg ccgttcccgc 81360 tccttgtccc gctggtctgg gcaggggatgccccatgcat gcgcaaaagg gccaccaaca 81420 cccacacagc acagatgcac aggtgcatggggcacacaag acggggtgga gggtggcttg 81480 ttagaaacat gaatgacaca ggtaacaagggcctctctag gagcagctgg ggtgagggga 81540 cagccataac ttgacaggga atggagtgtgggaagggttt gatggactca ggcagaaact 81600 agagaatacg gagtagctaa actcaaaggggtatggatcc aaaaagggtt tctataggca 81660 tgagtagcta agtcaggagg ggtatctagatctagtgagg gggtagctga gtccaaggaa 81720 ggagaagctg agtgaggaag tagctgggtgggccatcagc aggtctttgg ttggaggaga 81780 agagcagctg gaggcaggaa tatttagatccaggaaggga gcaattgatg ggatctgaga 81840 agcaatctga tccaggggaa gagtagctgggagagaagct agtgaagggg gttaactggg 81900 cttaaaatag aagtaggtgg gtagagatagagactggggt ggccatcagt gggccctggc 81960 agaagcagct agattcagag gagtaattgagagtgtttga gaggagaagc aattgaaccc 82020 agaatctaag ggaatgaata gatgtgtccagggaagaact atctggggga ggaagtagtt 82080 gtgtccagga aaagggaagc tggatggggcagaggctaag atggccatca atggacttca 82140 gggagagagg agcagcaggg agaaggagtatctggattca gggaaggagt cgttgacagt 82200 actttgagag gcaactggat ccaaggagagagtagctgcg ggagggagta tctgggtcta 82260 ggaaggagaa gagaagctgg ttggggagaataactggggt caccagcggg agagaaggag 82320 ctagggaagg agcagctgga tccagcagggaatagccaag ggaactgctg ggtctagaga 82380 aggagaagct gggtagggca gttattaagctggggtgtcc acaaatggac cccagagtat 82440 gaggggagca gctggggaat ggggcagctggatctagggt agggcaactg gctctctacc 82500 tctcttcctt tgtcggagct cacgaagtgcagcccggatg agcttccgct cttcaaagtc 82560 cgtgctctga tccagctgca tatagagcccatcattgcct acctggtgcc tgctggcctc 82620 tgccaacccc cagcccaccg gatctggctataccatcttg tccaagactc cttcatcctc 82680 aatagtcatc agctcctcag cgctcagagggctccgccct tctggtgctt tgttcactcg 82740 ggtctgctca gccccattgg ccgcttccactgctgcagcg agaggctctg ctggctctgc 82800 ttccatctgc agggtgggga gagggcatggactttaagca ggggtatggg tgaaactcat 82860 catgtctcca atggataggg aagcagatcctagggttgct ggcacgcctt ggaaataacc 82920 actagcctgc cagcctgcct gcccaaagatggccatgtca gcgtcagtca gggaagaggc 82980 actgacagtt ttgttgtagg gcttcccacgtaccccgaat tgtattaata caatggatag 83040 tgataataat gatgatttcc agtccatagtaagtgttgta taaacactag ggactttact 83100 gtccctattt aacagaaggg aaggccgggcgcagtggctc atgcctgtaa tgtcaacagt 83160 ttgggaggcc gaggtgggag ggatcacttgttgccagcag tttgagacca acctgggtaa 83220 catagcgaga ccgcatctct acaaaaacaaaaataaaaaa ttagctaggc atggtggtgt 83280 gcacctgtag tcccacctac tcagaaagctgaggtaggag gattacttga gcccaggagt 83340 tagaggctgc agagagctat gatcatgcagctgcactcca gtctgggcaa gagagtaaga 83400 ccctgttgca aagaaaacaa gaccggaaaaaaaaaaaaaa aaaacagaag gggaaactga 83460 ggctcagggc agctaactga cttgcccacagtctctctct aagtgtgatg cagcctggga 83520 tctgagctga aggcagccta actcctgaaccttagttcat tttgctgctt tgttcccagc 83580 cccctcccag gcaggctctg ctctgtgctgccagttcccg aggcctaggt cctcctgggc 83640 cagtgcccag gcagcacatg ttgccccccatctgcctgct accttgccaa gagggctggc 83700 ccggggcctg taggctcctg accaggtgtctgactggggc tgccctgagc caagacctct 83760 atgaagctct cctctgtacc acctccccctgcctcgcccc tgctggaaac catcctctaa 83820 ggagtctcta gccctgcagc cctcccagggcatctcccta gccccttgaa gacaaggccc 83880 caagccaact attatggccc ttcctctcctggcagggcct ctccgtctgc tataagggta 83940 aggagagctg aggtggcagc tgtttcagggaggcttggtc tggccagggt gcagggcggc 84000 agggagctgg gggctggggc ctgggtcatgccaggggctg ccaaggcagc tgccacacat 84060 gcctcagggc tggagcctgg caccctcttgccctagtctt agagcactag tgccccagtc 84120 ccctgtcaag atagataaac tgaggctcagagaaggtggt gacataccta aagtcaagag 84180 gaggcagagc ctggctcaaa actacccctcccaccaaccc agaagcactt acgagactag 84240 tgctgcgggt ggtgccggtg gaggagcggcggcgggtgct gaaggcaggt gggtgggcca 84300 cgggggtccc ggcatcctcg gcagcctgaaagagggcctc ggggtcggcg gcagccagga 84360 gcagctcgct gggctccagc tcaggctcaaggccggacac aagtgggacc cccagccgta 84420 ggctcagcac ctccacctgc ctgctcagtgcatccagccg ccggctcagt gctgctctct 84480 ctgcccgcag ctcttcagct gcccgggccaccggctccac ggtggctaca gctacctcgg 84540 ctgcctgggt cactgccacc cggcctgcttcagccaccgc ccgcagctcc tccagtgccc 84600 ggcccaactg ctcctcaagg gctgcggccagctcaggccc aggccctggt acccccggca 84660 tggtgctggt ggggactcta tggggggtaatggtggggca gtggcagggg ctgctgtctc 84720 tggctgagtg tctgagtctt tgcagctggtccgagggcaa aggcaagggc agcgggcctg 84780 ccccgcccct gcctcccagc ccgccaccagccagctggag ctgcagccca aatagaaacc 84840 tattctgggc tcctccgtgg aaggggcagtgggggagggg gggcctgccc aagcaggcgg 84900 atcgccaggc ctggctatag ccctacagaaatcataggcc tgcagcacag taagactgca 84960 tgggttctga agatcactga gatcggggccccatgcctca caggtgggga aactgaggca 85020 gggaacaggg aatggacctg gcctagccaccatgtacatt agctgtgaga atcagtctgc 85080 tggactccac agcctgtact cctttaccctttaccctaac tccagctgtt ttagacagct 85140 ggaacagatg ggggaaatgg aggcacagggaggcaggact ttgagtgatc tgctataaaa 85200 agtgtcttgg tcttacataa atgccctctggcctgcccat ggtgctcacg tccaaccaca 85260 gactttgagc aagcacatta tgggtacatcacctgtcccc tttggttcca gatgggtaaa 85320 ctgaggcaag ttggtggtgt cagacccaggtctcactgtg gcacctccca tccacctcaa 85380 gggcctcagc gggtcccccc accccaccccacacaatccc ttgtcagagg gcagctggat 85440 cctgcttttt tggaaaggaa gggtgctttatttccctcac tctctccctg tctcccctga 85500 gaaggcccaa agctggtcta gccatctcacctcagccaaa gtcccattca gtccctggtt 85560 tagcacagag ggcattacct gggcagccgggtggcccgct tggggatccc tttcccggct 85620 gagctcccgg ctagtggatc ctgggcttgggaatgaataa tggaagggtg ctgcgtattc 85680 agttcccaag gcacctgcta ggctgctgcctcacctgatt ggcgcccctc tgcctgtctg 85740 tcccccctca gagcttctgc ccaacccccacagggaggtt gacgcagatg ctaatcacta 85800 atctccaatc tcctaatggg ccaggctgatcttggatgag cagatgagct gctctatacc 85860 tcggggctga tgtccagtgt gggtgggcgcaggggcactg gggctgccac aggaagaggg 85920 gagcaagccc ttaccaccct ctctgagcctcagtttcccc atctgttcac caggaatgaa 85980 ccaaccaatt tcgaactaag gatcagagatcagcatccag gaagcttaac gccagtacag 86040 agtaagcttc cgacacactt agggactgatatgctagggt ctggccttag ctctgccacc 86100 gactggctgt ggtctgtgag cagccaccttccctctctgg gcctcggttt ctctgtgtgt 86160 gcagtagggg aggagcagag gaaccctgctagccctacac cctgaagcag tgtatgtgag 86220 gctgacggat ggtgaggctg gtggggtgaggaggggctca ccttgatgct gcagcctcct 86280 cggctactgg ggggggcatg gctgaagctggtgacatgag tgacactgcc cagccgagcc 86340 agggtcccag ggctgttgac acgggtgatggtgctcttgc ccccactact ggtgctgagt 86400 agggtcgggg gcgcccgcag ccccagtgtcagttctgagt ggggagaaag gtggctgtca 86460 ggaggatcag gtggagtgag ggcagtgccagacaaggttg ataatgccct cgctcccagc 86520 acaccctttg gagacaccct gagtcctggccgcagcacct gtcctgcatg cagaagtgcg 86580 gttgcaggca ctcatcccca ttggggaggcagtggggggc gcctacctgc cctctggttg 86640 cctgtgggca gcagcacccg gcctgtggaggcctggccac ggccgtcctt gatctcgatg 86700 gtgaatgtgg tcttcatact gccccctggctcggcagtgc cgacggccac gggcagcggg 86760 gcaccaggct cctctgaacg tgccacaggcccccctgctc tgttttcaag gggcctagca 86820 gccaagcccc gccccctggg gccctcctcctgggggcagc ttcgaagctg ggccaggggc 86880 tgggctactc ctcgttgctc cttgctgaaccgggaggagg tatcactggg gccccgagag 86940 gaggagccgc tggaggagga ggcaggggtggtgctggtga gggaggggcc caggagcctt 87000 gcgggggtca ggggacttag ggcagcctggggtgtgccat cctggagcct agcagccata 87060 ggagaatcag atgtgaactt gtggacacgatcccgcacag agccagcccg ctggaatgag 87120 gaaggtccgc tggcaagggg ggtggactctagaaggaaca ggagggctgt cagcaactgg 87180 gtgggacagg gtctgcacag atcctaggcagggtgagaat aggtagtacc tcggttctgg 87240 gctggttggc gggggctgag caccgacagggagcgttggc agggtcgggg tccagccacg 87300 tctggcaggt tggggagggg gtgatggccatgtggggaaa gagaaaagac aggggatagt 87360 gggtgtccac ctttcataat cctctcctctacacctccct agcttcccac cctttcctgt 87420 actcaacccc caccccacct ctccatcccctcctggatct cccacactcc ggcatcccca 87480 ctcggctgca tctctcctac aggcacctccttctcctgcc acactgaccc taggatgact 87540 tggacactcc tgggggccag gcgaggcttaggctggagga agggtgccca gatcctttct 87600 gcagatgggg aggggggaca gccctcctggccagtgctgc ccacagctcc agctgggaga 87660 tgggtggact cccttattgg ggagaagaatgtgcctgagg cccgttgcct ttcaaggctg 87720 caggggaggc ctctagccat gggggtggagggggaggctg gcctagctgg gggcggggac 87780 acttcagggg tggggtgcag tatcagggactgcatggacc tgaggaagct agagctgcca 87840 ggcacaagag cccattttct aggcagggaaagggaggcag ggggagggga agaaagatgc 87900 ctgtgactac ccctgctggg accctcacctgctctcttgg tgtcagaggg gcctctggtg 87960 gggctctggg cagcaggggt ctctttggggccagacagaa gctgcaaggg agaagaacag 88020 ggcctgagca aggcctgact cccagacctgctcacttgcc tggcatccct gcccctcatc 88080 cagactcacc ttgttgacca cctggccctcagtgctgggg agcgttggag actcctgagg 88140 ctcagggctg gtggtcttgg gtgggctggggggtggctct gggctgcctg gaacctcagc 88200 tgtaaggcac tgggcctcgg caggctccaatggaggctca ggagaggcag gggtgggtga 88260 actgctgggt gaggcaggtg agctggatgtgctcccaggt ggggctcgca gcaggagtgt 88320 cactgtggtc acatcctggc tggtgccttcaggggtgggg gttggctttg aaacctctgc 88380 ctgctgttcc tgttcctctc gctctggcacctgtaaggga cccacaggat gcaaccaagg 88440 ctccctaggc tttgaacgcc acccccaccactgagggcca ggctggcaag tgcccagggc 88500 agggcatgca aagcagagtg gtggggcatggcttcctgta ggcacacctg cgcaagcact 88560 ggcactggca tgctaagggc agtctctgatccccacttcc caatctcttg gcactaccta 88620 gccaaagggg ttcagagagg accaggtcctgatgtcagtg ggtgggtatg gcaggagacc 88680 tattggggac gggagcctta atagatccctggagtggagg ttcctgactc ctggcctcag 88740 cctggttcat ctggagtggg agtggggtcctgccaggacc gtggacccag cggcctctgc 88800 tggccacttg gggaacctgc atggcctgacctctcaccca cactctggaa aatagagtga 88860 actgtgagcc agctggggtc tgacatgcaggccccataag ccaaggtaaa gatgtgggct 88920 gtgtggaggg tgaggggcag ccctgggacgggttgaagca ggggaggtgc cagggccgga 88980 tttgcatttc tgggagatcc ctctgactgctaaatagagg ctggatggca ggggtgggcc 89040 ccttacagtg aaataccagc ctagcaaagacactcaggca ctctgtgcta ccggtatcca 89100 tgggcacagg acactgggcc actctcccaccctccttacc tcacactgtt ccagcctgtg 89160 tgccgctagc cccttgctgt cctctcttgagccactgttg ggacgcccgc tgtacaacct 89220 cccagccaag gtggcagctg gaagggaaggagcaagtggc aggtgagtga cagggaggtg 89280 ctgtggacag cagacagcag ggcaggggtggggccgggac aggccacata ccctcaatct 89340 cctgagcccg tacacggcgg atggcagctcggatcagctt gcgctcctca tactcaccag 89400 cgcttcgcaa ctgtgggtaa gagacaggtcgcgggtgttg ggctgtggag tccaggtctt 89460 cacctgccct gcccccatcc cctgccccagcctgggcctc accagtgcag tcaattcctc 89520 cacatcgttc atggactcca gctgccctgccagccgtgcc agggcagccc gctgctcagc 89580 ttcccgctgc tgagagctgc agagacatcatgactgtaac caccactgcc atggccaggt 89640 cgtggaggat gtgggctaag ggtaggagccagaacagagt acccagaacc ttggcagaag 89700 ggcatgtggc tgtgcacacc ctctaactgcacactgatac acatatgccc atggacgtgg 89760 gcactaatac cacacactca gacgtgctggctacatcagc acggccgcga cgccacaatc 89820 agtacatgct ccatgcccac aaacatctctgtttttccag aagcgtgtgt ggacgtactg 89880 ccattagcac atgcaatcca cagatacacttgtgctcacg cctgcctgca cacatgagct 89940 gagccagggc tcacactcac cttctcacccgcatgttcca ccccccgcta ctcactgcag 90000 ccagttctcc ttgttgtcct gccgctcggcacggaaacgc ttggatgcca gggcctcctc 90060 ctcgcgctcc agctcctgcc gctgcagttcccggatggct gagcggatgc gccgccgctc 90120 tgccagatct gctgtgacct ccagctgcagtgggtgcgag aggcaggtca ttttggctgc 90180 caggggcgga gggctggcac cagctgcccacggctctgcc tagggcacaa tgtgtggcct 90240 gtgtccactc cctgtgtccc aagctcttcacgtgcctgcc tgcccacgca gggtcccggg 90300 ggtagaccca gcccactgtt tcagggatcttgggtagtcc actttgcatt gtggttcaca 90360 gagcacacaa ctgtgagtgg acagccagaaactgcccact tgtgccaggt gccaagccag 90420 gcactccttt ctacaactcg attcctgcctctcagagccc agatccccaa aagtcaggga 90480 gctattgtag gaggaggagg gaggccaccctgtgggtcac taacagggtc cctagaggga 90540 aaggtgacag atgaagtcca ccctctgagcaagggaggct ccctggtcta gtcaccaaac 90600 accacagccc agctgggggt tgactgcttcatccacagat ggggaaactg aggacaggtg 90660 ctcaggagtc ctgcctggct gagggctattgtccccactg cactggcctg gacctagcca 90720 ccatggaaga agccagggtg cagagtgggaggaccaatcc cccagacata taaggtggct 90780 ggcactaggg gccaccccag ggccttatagagggcatccc tgggtgacag ctgcttctac 90840 cggttctcaa cccctcagtt cccgggaaattgggggtgac tggtctaacc aggttcagga 90900 aagaacacct tctctggagt gagtcagccaatcctgttgc ctcccccaca cctccaccat 90960 gtagagccac ctgctacata cagatcctccgtggctcaag ggagagagga ctggcccagg 91020 gttcccctgg aagatagtgg cagagataagcctccagtgt gggtctgata accagacggg 91080 agccagtaaa ggcggggtga tttcctctgtccccaccccc caaatcattc aggggtaggg 91140 ccaaagaacc ctctatcatc tccctttttagcgccccccc gtcattcctt tctgcttagc 91200 gggaaggcca ggtggcaagg gtggggatgggatggagata gttttcagca gggagtgtgg 91260 gctggcccaa ctcagccatg agccagcttgtcctagtctg aagagagcag ggagagtctt 91320 gggggaagag ccctccaggc tccacattcctgaggaatta tgagaagacc ccctgaaact 91380 caggccagag cccttagttg gttccagccctagtccaatc ctggctgggt gatcaagagc 91440 atatccctta aactctctgt gtcttggttttttcatttgc cagtgggtgg ggttgggaac 91500 agtgacttgg cctctcctgt acatagctgcagttgcaata agcatcaccc ccatacttgg 91560 ttctagccag tcaggaggag ggagagagacaagggggcaa atgggaaggg caggataccc 91620 cgaggcatca gtaacattta tggagagcctgtgagtcaaa ccctgtgctg agccccctac 91680 ttgtcctaag cccacaaaaa ccctagatactactgttatt cccatttgac agatgaggag 91740 attgaagtcc agggaggaca tgtgatttgctcatggtcaa atgacctgag ccaggatttg 91800 aacccaggtc tctctgactc cagggcctgccctaggctga agatagctct gctactgggg 91860 tctgtgtgtc atggtgggga cctcagggatcctggcactg tgttggagac ccctctagcc 91920 tggactagag atgctctgag gcctaaggaggccttatagc agaggcgggg ggaatgaggc 91980 tcactcccca gcccccggtg ctggctgtgtctcaggccta gagccttctg tggtacattt 92040 ggaggctggg ggctggaggg gacagagggtccagcccctt ctgtacagag ggtaaagagg 92100 cccagagggg caagggctag ccttttgtctcctaggtccc cattctcagt gctctgggct 92160 cggagatggg gtccttgtct ctgacaaaagcctgatgtag gaacttggcc acctctacag 92220 cacaaccccc ggagcttcag tgtccccatctggaaaatgg gagcctccct ctgatccccc 92280 aaagtgggtg ggcaaggctg gagactgacaacctcattcc actggtcacc ctctggcacg 92340 acccttccct ttgggcctgg aggcaaaggttggaccacag tgtctcctct gtgtgtcccg 92400 agttccaccc gcccaggccc caccgctgtgtaaggaggga gctgtgggag ggagggaagg 92460 aagtacaaag cgccattgtc taccgagggggaaggggaag gggatggggc ggtttccgaa 92520 actgcccagt gaaattctcc cgggaggaaagagggtgctt cctccccctg gggagccggc 92580 tctccgtgta ctctctgccc tcgctgttgggaacgcctgg caggccctga ggtctcactg 92640 ggcctcagtc tccccaacag cacaacggagggggctctcc aggctttcag tcccagctcc 92700 cccggttgcc catgggggtc ccgccggcggtggagggaag cctcgccagg gggcgctgaa 92760 ggcccgcagg ttctgcgacc gccctccctcgcagggcgcc gccctcgcct cgcccaccct 92820 gcctcgcgct aggcgccgaa ggggtagccaggtaggaaga cacccgctac cgcctgcttc 92880 agtgtccgga tctaaaggga agaaaccaaggtccccagga cacccagctg agtggcggag 92940 gtcgaactcg aactcgggac cgaggcagagggcgtcccgg cgggtggtgg aggggcacgc 93000 ggcgtgcaag tccccaggcg tccccattcctcccatcccc ggcccaatcc tcaagaatgt 93060 gcgggagccg gggccggaag cgactgcccgcgtccccaaa tcggccagac gctggggcgc 93120 agggcgggcg gagcgggcct agcttttccttatatggccc ggccccgcgg ggaggagccc 93180 ggctcgggac gcccccgttc ttgccacgaggccagcgggg gccgggccgg cgcgcggggc 93240 gcagtaatgg cgggcgccgg gtgctggaggagccgctccc ggggtcggaa agacttcgag 93300 aggcaccgat cccgagaccg gggcaggttctcatctgtcc tttcccagag attcaaccac 93360 tgctccagct tctctccaaa actcttttccagcgccgccc gagcctcgct taagagaggg 93420 aggtggcggc tgaagaaccc tgagcctgcctgtggatacc ttgagatgag gatgtgcggg 93480 aaccaggcct ggcattccct ctttttggactgtgctgcct ctacgacccc cactgggact 93540 tggacttcct gagggaaggt cgaactgactggcgggcacc tttggaaacc taacctcatc 93600 ccctccaggc tgcacacatc ctgcggtgatagtggagagg cagacaccca gagagtctaa 93660 tgcgctggtc cgagaacata caggcagagtgccttgggga ggtcatggca gcagctgggc 93720 actgcccagt ggctgggcta cgctggttggttccagcctc tgcctgcggg ggaaggtatg 93780 agagtggggt gggtcacttg tcttctaggtaaagtaaatc tttaatttac ccccatggac 93840 aagggtcagg gactgaggag atggagctcctctggcccct cctccaggtc aggctgcctg 93900 gcctttgggg ttggggaagg agccctgccccactgggttg ccctacggcc tctgtgcatg 93960 gaggtagaca gggctctcag gaagaggaacaagaaagggg atggagtggg ctcatctttc 94020 ctccacctga gatctgggtc catgcctcattctgtcccca tgccaactct aggacctaga 94080 gcttgtgtgc aaacacatct ccctccctcccttcatttta caggtagagg aactgagact 94140 caagagtaga aaaatgagat gagaagccacagaatccata agggcccaca aaacctgtct 94200 ctctcttatg gcctcgtcca gccttgactttcccaggact ctggtccccc gtggcccact 94260 atggggttgg gattttggca cagctccttcttagatgggt gtccttgagc aggtgatttt 94320 aactctcttg agtcgcagtg cccaggctttcagagctgct gtgattattc tgtgacatgg 94380 tatacccagt acccagcctg ccccctgccaggccttggca ttattaatca ttgctgctac 94440 cattatcact gggccagctt ccaggggtgggcattgcccg agctattgct ctggagaggc 94500 atatccagcc tccccacacc tgtggctgcatacgggcgag tctacagcag ttactgttta 94560 aacaggtggt ggctgtggag ggttgggagggactaggctt cagtaccagg catggacagg 94620 cacatgccac aagggcctct gcatcagccacatggaactg gcctacccct gttcccatgt 94680 ccccctcctc ctgacctttc ccccatcacttcttcctgtc agctgagagg taccctggat 94740 tgaccctgcc tctctggctt ggctttcctgtccccacagt gggtgatggg gccacttacc 94800 agcttccgaa gggctccctc atccagcccagctaaggcct cgtccgccat ctcgctggcc 94860 cctagctccg tcggttcctt tctggtgagatccccagtgc ctgtggcacc tgtcaccagc 94920 tcagagaatt ctgcagggga cagacatgaatcaggcatgc tggggcttcc agaaaccaca 94980 ggcacttagg ctctgtgcct tactttccctctctaaccta ggagcgtcca ttactgtccc 95040 atcctataat gtggctcctg gctggaagctgccctctgcc ctagggtggt ttgctggaaa 95100 actcaccaaa cccagggtag ggggtctctggttccagccc tgccagcttg gccgccagtc 95160 tgctgtgtgg cctgggatgg actctcatcctgtctaaacc tcaaaacagg gagggcaggg 95220 acctggattg agaagccagg gcctggcaagacccacccaa gctgtgctta ccaccagggg 95280 gtgcactcca gtctccagtt tcctgccccacccacccatc cacagggcct acccagcccc 95340 cacccactcc gcaggctcag cttctggctgtgggctgaac ccgtagttct tgctgccacc 95400 accactgtca ttcccccagg tataggaaggtacactgtgt cttccgattc ttggagccag 95460 ctctgctgtc cagacctcct gaagccaggtgtccaggcac ccagcacctc ctgccaattc 95520 atacagaatt caattcccca cctggaagggctttcagaag ctgacctgcc caacccctgg 95580 atttcaggca aactgagaag attggagagggccaaggatt tgtcactgag caaggaggaa 95640 gccaaagact tagagggcag agaaggatgtaatcaaaatc ttcgtcatct ccggcttccg 95700 aagctccctt ccaaagtgcc ctcaagggcctggaacactc tcagtgacag aggcaagagc 95760 cccatcttgc cccagtgctg cccatcaaaatggaccccta aatcctggcc cagcctccca 95820 gcgcagatct ctccttcctc ctgtagccccaactaatgtc tgtctggaat ttgaggggcc 95880 ctggtctggc acactgtgga tgcttagttaatgtatggtg actgactaat gtgtggcccc 95940 aggcctgccc cccacctcct gttgattcatctttcaatca tcccttccct ctcttcagaa 96000 cagtcacttg ggaagtcacc ccatacggtgcatgggtggg gggtgagggt taccgctcca 96060 cacagttggg gtgtgtgggt cccagcctgttcaagtcact gcttgttccc cctcccatcc 96120 tggtaggctc agaggtgtca acctcccaatctctgcctgt taggatcctt gcctcttacc 96180 tagttactct gtctgggtta aacctcttcaagactgtcca gtggtcacca gccttaggtt 96240 ctgcggacat tctgattccc cccatgtctgttcttctatg gggcagctga ccctaatgcc 96300 taatctagga cacccatggg attataagaagatccctgcc gctgctcttc tccaatctcc 96360 ctgtcacaca gtctggggtc gccggacattgtgaggggcc tcaggattct gtggcagctt 96420 ccccagggtt tctgccgcca cagactagcgcccctgtggg gcgtggagtc tcttaggaat 96480 ccgggggcgt cttcccccaa cagtctcataactttatccc atggcttaga cctctcgtat 96540 gggtgggggc tcccaggtct ggacgttccagaactcctgt ctagacatcc gggttccacc 96600 cccggacacg ttggggcagc accaggatcccccccgaggt ccgcacaccc acctctcagt 96660 ccagcccacc cgtccggcgc aggctcggcttagctctttc gggacccgac agacggatta 96720 gacacgcgca ggccggaggt gccgcgacccgctgtcccag gcccgctcag caaccgtccc 96780 ctggattctg cggagagctg cccgtccagccgcgccagca gcccggctgg ccccgccctg 96840 ccccgacgcg ccagccaacc ctcgattgggtacctcccac tctcgtgccc cattgggaaa 96900 attcaatttg acggccacgc cccgagaggaaggccccgcc cctcgcgggc cagggaggtc 96960 ggaaattggg agtcttgggg tcgtctgcctcggtggcttt agcgagtcgg gtgggcatcg 97020 gcagggggac gcaggctctg cgccaagtcggggggggcgc cccgagccga ggtaagtttc 97080 ctggggtcgt aggagtctca gagccttcaggacagcccct ctccgccctc ctctttgttc 97140 ctgagaccac gtcccctccc tcgactccacccctttctcg cgtcagtgtt taagcttggc 97200 cgccgtccct aggctgcttt cgggacacctggtctgagcc acctcagagc agggactgag 97260 tgactggcag caccttgacc ctgtgttggagtgccgggac catctcaggt ggagcagaat 97320 caatcacaca gcacgcctcc cccagcccacacacctttga acagacattg ccttcttgta 97380 gcatgcttct accttccaag ccctgagagtctgcctttag gagcgctgga gtcctaaata 97440 gggaatatgg agtccaggct gtcattcagcaaaaggggga aattgaggcc cagagagagc 97500 tgacatgtcc aagaccaaac aaggaatcagccagggtacc caggaggtca gatccacaag 97560 gcaaagctat tccatcttca gtgccagaggccctaaagcc gcccttgggt ctccatggag 97620 actaaagtgg gtggagttgg gaggatggggtctggagtcc tgtcaaataa aaacaataac 97680 aaatcattta ttttgtactt gccatgtaccaggcatataa tgcccataac aagcacatga 97740 gaccatgact attgccccat tttacagatgaggacaacag ctgataagta gtaaagctgt 97800 gattcatacc cagcaccttc tgagtccagaccctgctttt aaccactata atgtgggatt 97860 ctggggaggt ggtttcagcc tgttaacccagaagagcccc ggttcaggtc ctctgtgaca 97920 ccccccagcc cccatctaag gaaaggcccagtctccacac tgagagtctt ttccatgtgt 97980 catttcattt catccccaca cccctgagaagtggtcccat tttacacatc agaaaaccaa 98040 ggcacgggcc aggtgcggtg gctcatgcctgtaatcccag cactttggga tgccaaggca 98100 ggtggatcac ccaaggtcag gagttcgagaccagcctggc caacacggca aaaaccccgt 98160 ctctactaaa aatacaaaaa ttagtcgggcaagtggcatg cacctgtaat cccagctact 98220 tgggaggctg aggcagtaga atcacttgaacctggaggca gaggttgcag tgagccgaga 98280 ttgtgccact gcactccagc ctaagcgacagagcaagatt ctgtctcaaa aaaagaaaaa 98340 agaaaatcaa ggcacagaag aaagcgacttgtcaatgcta cacagcagga gaggcaaaca 98400 gagctcactt cggaggacat atttcaaggtcctaggcttt ctctacctgg gcgagatgcc 98460 atgttattat ccagaacgag ggtcaggcgccctctaagac caattctgaa tacttcaaaa 98520 ttcacgcgtc ccttgggacc tccccttcatgcagggcaca cctaggccac ctctgatttt 98580 cagggcctgc ctgaatggcg gtcaccagctccaatgaatg gcctgctttg tgctaatgcc 98640 ctcctttctc cctgccctac tgtaggctaggaggaatggt acaggtgagt tcctccatgc 98700 ttggatttac tgtctggcac atgcgctcactagcccttgg ccctatggaa gggatgtgtg 98760 ggtcctgccc cttcaagccc ttagtgcctgggtccacctc cagacatacc cgcctgcctc 98820 tgtcttcctc tctgcaaggg agtgggggtgatctagagat caaagggcag tccggtacag 98880 tgctagggaa gtttacagct acagccgaggaaagagtaaa catcccgtga cgagggcccc 98940 agcatttgct gaacacctgt tgcatgtcagacgtggggct cccactactg ccaggtgacc 99000 actgtgcaag ataggtacac tctgattcgacagaggaagc tgaagctcag ggaggtgaag 99060 gcaccttggc ctagtaaagg cattcagactaaagtggaat tctgcctgat gctgaagccc 99120 cttccctcca ctttgctgcc actaggatgggggaagctct ggaagacttc ttagggaagt 99180 ggtgtataaa ctgtgtgtca cacttgtttttattttattt tatttttttt ggagacaggg 99240 tcttgctgtg tcccacaggc tggagtgcagtcgcatgatc acagcttacc atggcctcaa 99300 actcctggct caagcaatcc ttccatctcagcctcccaag aggctaggac tacaggcaca 99360 caccaccacg cccagctaat ttttaaaattcatcccacat agaagagggg gaaaggcatg 99420 aaagggcatt tgtggcagag gaacagtgtgagcaaagacc aatagtctgg gaaaaggagg 99480 aggataggct gtgggcggag caggaaatgtgggtggttct ctttgccaag gattctgaat 99540 gccagatgag caggatgaat gtatcttgtgggcaccagag aggcctgggc ctcagcctgc 99600 cccctgtaaa atgaggtgat tagactggtctgcttcaagc cttcctaggg caaggggctg 99660 tcacagaaag ggtctactct aggttcttccaggttcaacc ctggaaaggc agaatgggaa 99720 gtggctggag cagctcagag gctaggggtaatattttgct ccagagctca agtctgagaa 99780 tgactatttt accaagctgt ctgtgttgcatccctaagtc accctggcta accctccacc 99840 cagtcagggt ccttcagaga aagcccaggccttgggtcag gaggcaagaa gggtgatggg 99900 tgtcttaccc ctggctccaa ccctaggtaagggttggccc tcttggagct tcaacttgct 99960 catatgcaca atggaggagc tgtgccttgggctctctaag cctctctccc caggacagca 100020 ctgtcattct ggagacggga acagcattagcaaaggaacg gaagtaggat tgtgacgacc 100080 ttgttgggca acagacaggc aggtgaggctggagaatgga gcccctagag gtggatggtt 100140 cttgttgggg ttggctggat ccaaggggtatgaccttcct ccttatgtgc agaactggat 100200 gcgtcctagg tcatggccag cagccctcggagtgggactg aggacctgct gggaaaccag 100260 tttggcaagg ccatcatctc caggatgtcatccagccgct gtgttctctg ggcaacagtg 100320 ccaggcaaac ttctggccct gcaggaggagaaggggcctc agatgcccac tgggcagcag 100380 tgaattccag gagacccagc ctcacagacaaaggagaggc aaggggctgg aacaggaagg 100440 agagagttct ggatgtgcca gcctggacctctttagactt ctgggagtcc ctgatgcctg 100500 ggcgcaggga gtgggggtct aggctcatggtgggacacta tgtaattgct acctgatggg 100560 ttggacactg gctcctgatc atgcttatactacatgtgtg gcaattttgt taccactatg 100620 accttcacag cttgagtcct gtgaggtaggaccaccatta tacagataag gagacaggct 100680 cagaaccctc gttcttttgt tgtttttttttttgttttgt tttgtttttg agacagagtc 100740 tcactctgtc gcccaggctg gagtggagtggcacaaccat ggctcactgc agccttgacc 100800 tcccaggctc acagtgggac tacagacacgtgccaccatg cctggctaat ttttttattt 100860 tttgtagaga caagggtctc cctatgttgccggggctagt ctcgaactcc tgggttcaag 100920 aaatccgcct gccttgacct tccaaagtgctaggattaca ggcgtgagcc actgcgcccg 100980 gccagaacat ttgttcttaa tcaccatattctaccatcca ccatttggaa gctccacttg 101040 gatgacgcct gagcactggg gagacctgggcctcagtctg cccatctgta aaatgagggg 101100 gtttgactcg cctccttcag gccctcctagggcaaaaaac tgtaacaaga agggtctaga 101160 ttcttccagg ttcagctctg gactggcagagtagggagta tctggagcag ctcaggggct 101220 gagggtattt tggctccaga gtccagtccgagaatgaata ttttaccaac ctgtcagtgt 101280 gggatcccag caaacccttc tctctacttctgaacatagc acctgaatct tggcatcaca 101340 gagtcctaga tacccacctt atggttcaaataggtaactg agtcccagag aggacaaggg 101400 acaggcttca ggtagtgtag caaatcaggagcagagccat tctgcatccc agattctcaa 101460 cctctcaaaa ctttgtttcc tcctcagggcctggcacact taagcatgaa ataactgaca 101520 catattgagt gcctatggca taccatgcactcatgtaacc atcaccacag ccctataaag 101580 cagatgctaa tgttctgtcc cttttatgggcaaagaaact gaggctcaga gaggggaagt 101640 catttgtcca agttgacact gcatgttggtggtagcgaag ggatttgaac ccaggtatat 101700 aggcccttcc ccctcagcag atccagtaagcctcactgga ggcatgaaga cctgtagaca 101760 gcggggtgga tggctccttt gccggttctgaaggcacgca gtgtccaatt cagagtttcc 101820 acgcaggcct ggcctctctg gggcagggagaaaagtgctg aggctgcaga agggctctgc 101880 atcttcccag aggaggcggc cacggtgggagggagtgctc tgcaacaacc tcagagccaa 101940 gtgtagacgt ggcggctgga ccagctgcaagcaagggaag gcaggcaggg tggggcccaa 102000 acccaaaccc agcctccaag ccgtgttcccagccttccgc cagccaggcc ctgccctacc 102060 cgcccttctc gatccccatc tggatttgagatgaggacgc cgggcctaat aatagccaaa 102120 tggcacggag gcagtgcctg gagccactgccagttggggc ctggggtccc ccatggtctc 102180 atattggcct ccaacagggt tcagaactttaaaagtactg cattccagcc tgggcgacag 102240 agcgaggcct tgtctcaaaa acaaaaacaaaaacaaaaca aaacaaaaca aaaacccttt 102300 aaaatagcaa ctgcttatga agtttataatatgtgctggg cactgggcta aagcttagcc 102360 cacagtaact tacttattcc tcaccctacccccactggct aagactattc cttttttttt 102420 ttttttttaa gacagagtct cgctctgtcacccagactag agtgcagtgg cgcaatcttg 102480 gctcactgca acccctgcct cccggcttcaagtgattctc ctgcctcagc ctcccaagta 102540 gctgggatta caagggcccg tcaccacgcctggctaattt ttgtattttc agtagagacg 102600 gggttttgac atgttggcca ggctggtcttgaactcctga actgaggtga tccacctgcc 102660 tcggactccc aaaatgctgg gattacaccgcgcctggccg ggctaagact attcttagcc 102720 cttttgatgg atggaacact gcccctgatgataacaggaa cttggcagcc ttcaattgct 102780 gagcatgcac actgtccctc cttggcactctgctaagcac tttctttgta ttttcccatt 102840 gattccccat ggcattatga gacagatgctaatttcttta gacgaagaaa aaaaatgagg 102900 cccagagaga aaagtgactt gcccaaggtcacacagctat aatggacaga gtcgagactc 102960 aaacctagga ctttctaact gtagagaggctaagacctta gcttctggaa acagacaaac 103020 ttgagtacgg tggggacatc actgctccctagctatgcag ccttggcaag tcacatcacc 103080 tgcctgaggc tcttgttttc tcctctgtaaattgggggtt tggttgagat aatactaaca 103140 ctccctgaca gctattaagc ccaccttgggtgtaataaaa taggtaattt acagcacacg 103200 tttccacggt gcattccctc agtcaattctcacaatagcc cccaacgtta ggactcctct 103260 cttccagcac ctgtgttttg ttgttgttgttgttgttgtt tttgttgttt tttgagacag 103320 tttcactctt gtcacccagg ctggagtgcaatggcacaat ctcagctcac tgcaacctcc 103380 gcttcctggg ttcaagcgat tctcttgcctcagcctcccg agtagtgagt agctaggatt 103440 actggtgtgc accaccacgc ctggctaagttatatatttt tagtagagac aggatttcac 103500 catgttgtcc aggctagtct tgaactcctgacctcaggtg atccgccctt cttggcctcc 103560 caaagtgctg ggattacagg tgtgagccaccatgcccagc cccagcacct gttttataga 103620 agggaaatgt cagtctcagg gaggggaaggcatttgccca aaatcaatag caagtgagtc 103680 aggacttaag cccagggctg tgattctagaggctgagctc ttttttattt tttaagacag 103740 gatctctgtc acccaagctg gagtgcagtggtgcgatcat ggcacactac agccttgacc 103800 tgtctgggct caggtgatcc tctcacctcagcctcccgag tagctgggac tacaggcact 103860 caccaccaca cctgactaat ttttatagagatggagtttc cccatgttgt ccaggctggt 103920 ctcaaactcc tggtttcaag taatccgtccacctcagcct cccaaagtgc tggaattaca 103980 caggtgtgag ccaccatgcc caggcaggcatgtgactatt tttggccaat agaatatacg 104040 gaagtggcat tgccagttcg aagcctgggtgttaagagat tgggccttaa gagattccac 104100 ttattctctt ggaactctcg cagctgttatgtgaacaagc ctgggctatc ctgcctaaga 104160 gaccactgga acagggacta gttatcctagctgaagctgt cctagtcagt caccagctaa 104220 tccaatagct gaccacagat acatgagtaagcccaactga gaccagaaaa atctttagct 104280 gagcccaggc taaagtgcca atccatgaaatcttgagcta aaaaaacggt tgctgtttta 104340 aggcactaag ttttggggtg gtttgttatgtagcattgtt gtggcaattg ataactgata 104400 cactgtttta ttcagtgtaa ttaatgctgactgctgtaac aaaccaaata tctcagtggt 104460 ttaacccaat cagagtttat ttctcacccctgcaaagtct gatacaggtt ggggctctcc 104520 cagggagctc ttttccaagc agtgaccttgcccccgaatc ctgcctccac cccaggcttt 104580 ccctggaatc tattcctgaa tcctctgcatgtggaaaggg aatcagaaaa tcaaaggagg 104640 cacatccaca cttaactgcc tttgcgcaggggtcacgtat aatttcactg gcctttatgt 104700 agtcacgtga ctctactaac tgcaggaaaaatgagaacat gaccttcctg tgtgtccagg 104760 aaaaggaaac aggttacaga acacaaagcattgcttccgt tacattcctc ctgttgtggg 104820 gctggcgtgc atgcgtgcat gcgtgcgtgcgtgtgtatgt gtgtctgtgt ctgtatgtgt 104880 ggtgggagtt ggaggggcat gtgtgttaagcagagaatta acatctataa agaatcaaca 104940 gtggtgcatg cctgtaatcc cactactctgggaagctgag gcaggaggat cgcttgagct 105000 caggaggttg aggctacact gaaccgagatcatgccattg cactctagcc tgggtgacag 105060 agcaagaccc tgtctcaaaa aaaaaaaaaaaaaaaaagag agagagagag aatcaacttc 105120 agcacctacc atgtgttagc ttaaataagggacaagttat aggtaaagaa tttgaggctc 105180 agcttaactg gtcctggtgc cgcacgcctgtagtcccggc tacttgggag gctgaagtgg 105240 gaggatcact tgagcctagg aggttgaggctgcagtaagc agagattgcc cactgcattc 105300 cagcctgggt gacagagtaa gaccttgtcttaaaaaaaag aaaaagaggc tgggcacagt 105360 ggctcatgcc tgtaatccca gcactctggggggctgaggc gggcagatca ccagaggtca 105420 ggagttcgag actagcctgg ccaagatggtgaaaccctgt ctgtactaaa aatacaaaaa 105480 ttagccaggc gtggtggcgg gcacctgtaatcccagctac ttgggaggct gaggcaggaa 105540 aatggtttga acccggaagg cggacgttgcagtgaactga gatcgtgcat tgccctccag 105600 cctgggtgac aagagggaaa ttccatctcaaaaaaagaaa aagaaaaaaa gaatctgaga 105660 ctcagaaagg ttgaggaact tgccccaaatcatacagcaa gccagttgag tagctatttt 105720 gcagtagtga agggctcagg gagatctggagttggacaga tctaggtgcg aatcccaact 105780 ctgtcaattc tttactgtgt gacatttggcaagttactta atttctctag gcctcagttt 105840 cctcatccac aaaatgggga gctaatacttccaaccttat aaggttggga gtgatcattc 105900 acggagcttg catgggatgg ggatcctggtacatgggact tacataatga atgtcagcca 105960 cataggcaga aatgatgcta tctctgatcttaccctgcca gggtccatga atttggccaa 106020 ggggatttat tatgttttgg acaaatcctatcccttccct ctatctcttg tggtgtaaat 106080 ggttttattt acttcattaa gagatggcaatatggctaag tgtggtggct tatgcctgta 106140 atcccagcac tttggggggc tgaggtgggaggatcgcttg agtccaggag ttcgagacca 106200 gcctgggcaa catggcaaaa ccccatctctacaaaaaata caaaaatgag ctgggtgtgg 106260 tggcatgcac ctatagtccc agccacttgggaggctgagg tgggagaatc ccttgagcct 106320 ggaaggtgga ggttgcagtg agccgagatcatgccactgc actccagatt gggtatcaga 106380 gtgaaactct gcctccaaaa aaaaaaaaaaaagagagaga gagagagaaa gagagagcta 106440 gaactatttc cccagttgaa ttttttttaattaattaagt ttttaatttt ttgagacagg 106500 gtctcactct gtctctcagg ctggagtgcaatggcgtgat cgcagctcac tgcagcctcg 106560 acctcctggg ctcaagcgat cctcccacctcagccggtgc atgccactat gcccaactaa 106620 ttttatgtat tttatttttt gtagagatcaggtctcactt tgttgcccag ctggtctcaa 106680 actcctgggc tcaagcaatc ctcctgcctcagcctcccga agtgctagga ttacaggtgt 106740 gagccatgat gcccgctcca gctgaatatttgttactgaa caaaccttca taagcacaaa 106800 gcccctgaac acctatggct gctgacacatgcctgaaatg cctccattat tgcttttttt 106860 tttttttttg agacagggtg tagctctgttgcacaggtag gagtgcagtg gcgcaatcat 106920 ggctcactga agccttgaac tcctgggcgcaagcaatcct cctgcctcag ccaccaaagt 106980 agctgggact acaggcacac accaccatgtctggctaatt ttcttatttt ttgtacagat 107040 gggatcttgc tgtgttgccc agactggtctggaattcctg gcctcagcaa tactcctgcc 107100 ttgcctccca aagtattggg attacaggagtgagccactg cactcaggct taaatcgttt 107160 tcttttcttt tttttttttt tttttgagacagagtttcac tctgtcaccc aggctggagt 107220 gcaatggcgt gatctcagct cactgcaacctctgcttccc gggttcaagc aatcctcctg 107280 cctcagcctc ccaagtagct gggattacaggctcctgcca ccacacccgg ttaatttttg 107340 tatttttagt agagacgggg tttcaagatgttggccaggc tggtcttgaa cccctgacct 107400 caagtgatcc acccacctgg gcctcccaaagtgctgggat tacaggcatg agccatcgtg 107460 cccggctggc ttaaataatt tttaaagttttgttttgaac aggtagttct gggaggtcag 107520 aggagttatc tctcaggaga taattatgctcaagtctgga agataagaaa ttgttgaaca 107580 aaaaactaag ttggtctcga cgtgggggtgggggtgttcc aggcaagggg aacagactac 107640 gcaaatgtcc cgaggcagga acaatctccagaaactgatg gaagaccaac gtgagtgaag 107700 tatgaagggt aagggagaag tggggtttggatggggagag gggaaaggcc cagactgaaa 107760 ggcccctgtg ggaaccttca caatttgcagggcctggtgc aaaatgagaa aacggagctc 107820 cttgttcaaa aattctgaag tatttcaagatagtgacagc agagcattac accgaccctt 107880 cattacgtga agctggccct gcccatggcccatagtaaga ggaaaggact ttcatgtgag 107940 ggctgcaggg agccatggaa ggtttttgagctagaggtga tcagatctga tttgcatacg 108000 cttcagttgc tgtcctcact accccacacctggatgatgt gtgtctctgc acaggtggcc 108060 tgcttcactt tcctcttcaa catgtcactcccctgctcaa gaacctgggg tggttcctac 108120 ttcctattag acccagccca gattccctatccagacaccc agaggccctt caaaatcttc 108180 ccttactgga tttagttaat ctaatgtcaacaaaggctgt gtgctgaatc ccagagagat 108240 gatgaatcaa cccaagttca cacagcaattataggagagc aagtcagggc tggaacccag 108300 gtttcctgag gtcggcccac ccagccctgagcgagggtgc agtcctatga agtgttttgt 108360 gtcccccatc ctagcacaga gccatgcacacagttaggtg ctcaatctgt gcctgtggcc 108420 gtgagttcgt tcctcttagg gcacatctctgccagggcat gggtgtccca gaatccagga 108480 tgcagttagc atccttcctg actccttctctccctcgtcc ctacctctag gcgttcacca 108540 agccccaccg cacccaggcc agctggccaggtcttgccca tagacttgtt gtttggcctg 108600 tgcagtgttt taaagctttt cgaattcatcgttctaacat tttaaaaaat ctggaaactt 108660 cacatggcaa tccccatctt gtgtctctttgcaaagtctc aagcctgggt ctgggttcct 108720 ttggggaggc agttctctcc aacctctgagcttggggtgg gtgaggtggg gaacggtcgc 108780 tctagtcccc agcggggcgc ctgaatttgggactttgaag cgagagtggc ctaattacca 108840 ccaaggacca ataaggatcc tggaagagagcgccctagtt accaccaagg accaataagg 108900 atcctggaag ttgattcaat cagacgtataataacccctc cttctggagc ggggccaggt 108960 gggggcaaac cccgcctccg gtcttctaacaacagggagt aggaggggtg ttttgcccta 109020 aaccttacaa ctagccccaa cctgatgtttgacttctgaa tcgcttaggg cttcatagat 109080 aagatgaatg cccctgagag aggccatgctgctttctctc ccctggcctc tgcctttgct 109140 ttcttctccc ctgggactgt gctcttcaaccacatcttca ctctggctgg ctccagatta 109200 ccattcagat cttaactcac acatcacctccttagaaagg tcttcccaga gcacgtatct 109260 gaagctcccc aaaattactc tgtactgtaattactcccca tcacagcact gacgatcgga 109320 aatgattaat ttttttgttg tttgtctcctgctagactgt gagctctgag aagccaggga 109380 cttgggtttg tctcgctcaa cacggtccccaggacctaga aaggatctgg cgtcaacgaa 109440 ggggctcaac acacgtgtgg aacaaatgaaccactggatt cacaaaacac ctttccctga 109500 aggatgcatg tgaccccttg gtcagccagccagcatgggt gggagccagt aaggaggcag 109560 ccaatttgca attagggagc aattaataactacctaattg gtacaaaaga cagctgaggg 109620 gctgggagga gaacaaggga atgaagctcagaaaggagcc tcaggtcttt cttggaaaat 109680 actgggagca ggcaatgagg aatccccggggtaacatttg aaaacctctt ctgttattgg 109740 agattcaaat gatcagaagc tcccctaaaaggacttggtc cctttaaaac attttttttt 109800 ttttgagatg gagtttcact cttgtcacccaggctagagt gcaatggcgc ggtcttggct 109860 gactgcaatc tccgcctccc aggttcaagtgattctcctt cctcagcctc ccgagtagct 109920 gggattacag gtgtccacca ccacgcccggctaaattttg gatttttagt agagatgggg 109980 tttcaccata ttggcccgtt ggtctcaaactcctgacttc aggtgatcca cccgcctcgg 110040 cctcccaaac tgctgggatt acaaatgtgagccactgtgc ccagccaaaa cattttttaa 110100 tggtttgtag agatgagatt tcgctatgcccaggctggtc ttgaactctt ggactcaagg 110160 gatctgccca ccttggcctc ccaaagtgctgggattatag gcatgagcca ccgagcccag 110220 ccaggacttg gtcctttaag aagcaggtgtgggccaggcg cggtggctca tgactgtaat 110280 cccagcactt caggaggctg aggcaggcggatcacaaggt caggagatcg agaccatccc 110340 ggctaacatg gtgaaaccct gtctctactaaaaatacaaa aaaaaaatta actgggcatg 110400 gtggcaggcg cctgtagtcc cagctactcaggaggctgag gcaggagaat ggcgtgaacc 110460 cgggaggcag agcttgcagt gagccaagatcgtgccactg cactccagcc tgggcaacag 110520 agggggactc gtctcaaaaa aaaaaaaaaaaaaaagaaga agaagcaggt gcgccgggcg 110580 tggtggctta tgcctgtaat cccagcactttgggaggcct aagggggagg atcacgaggt 110640 caagagatca agatcatcct ggccaacatggtgaaacccc atctctacta aaaatacaaa 110700 agttagctgg gtgtggtggc acgcacctgtagtcccagct actcaggagg ctgaggcagg 110760 agaattgctt gaacctggga ggcggagattgcagcgagcc aagatcatgc cactgcactc 110820 cagcctggcg acagagcaag actccgtgtcaaaaaaaaaa aaaacctttc tggtcatggt 110880 ggtgtgtgcc tgtagtccca gctactcaagaggctgaagt aggaagattg ttttagccca 110940 ggagtttaag cttgcagtga gtcatgatcacaccactgca ctccagcctg ggcaacagag 111000 acagactctg tctctaaata aataagtaaatcctgcctta gattaaaatt gcaggccagg 111060 tgtggtggct cacacctgta atcccagctctttggcagga cgaggtgggt ggattgcttg 111120 agcttaggag ttcgagagcg gcctcggcaacatggcaaaa ctctgtcttt acaaaaaaat 111180 acaaaagtta gccaggcatg gtggcgtacacctgcagtcc cagctactca ggaaactgag 111240 ttgggaggat cacttgagcc taaaaggttgaggctgcagt gagctgtgat tgtgccactg 111300 cactccagcc tgggcaacag agtgagaccctgtctcaaaa aataaaataa aataaaacaa 111360 aataaaaaaa attactgttg gattaattaggaggtttgat atggagtaag tcatcctttc 111420 atgttttgaa gtaactttaa agtgtgtccactcagtaaga cacaagtatc catttgggct 111480 tcttcaatat tctatggggt ttggctgggcacggtggctc acgcctgtaa tcccagcact 111540 ttgggaggcc aaggagggcg gatcacttgaagccaggagt tcgacaccag catggtaaca 111600 cagtgaaacc ccatctctac taaagatacaaaaattagcc aggcgtggtg gtgcatcact 111660 gtagtcccag ctacttggga ggctgaggcacaagaattgc ttgaatctgg gaggtagagg 111720 ttgcgtgagc caagatcgtg caactgtactccagcctggg cgacagagcg agactctgtc 111780 tcaaaaataa aataaaataa aataaaatattctatggggt tcaagagttt cctttttagg 111840 gccaaagcat tattattgga ggaaggcaatccctacttct cccacttatt tctgccatag 111900 gaggaaggtt ctcctgccca acacccacaggcccaggcac ctggaggcaa ctctaaaaac 111960 agcaggagac tactgaagga aattgtccatctctatgagg cgctccttgt gtctccaaaa 112020 tttattaaat gacatcacag taaggcttggcaagtaggat aagggagtta gaccagggag 112080 gacagacaga agtctgcagg cctgaacacaggcaggaagg aaaagggaaa tgcaaacagg 112140 agaggagagg ccagagctga gcactgcagaaggagaatga acaaccctag tttgtattac 112200 agaacacgtt cacaagtacg gtctgcctttatcctcagca gttcttactg gtaagatata 112260 atgatatcca ttttatagat aaggatcctaaagcccagca aggtcatgga tctacacata 112320 actgagccac acatcttaga tcagtgctttttctgcttgg cacaccccac agggactggc 112380 acataatggg taaagagttg acatttactgaagaaaagta gacggcatgc atttgacagc 112440 acttaaaaaa aaaaatgtag gccaggcgcggtggctcacg tctgtaatcc caacactttg 112500 ggaggccgag gtgggcgaat cacctgaggtcaggagtttg agaccagcct ggccaacatg 112560 gtgaaaccac gtctctacta aaaaatacaaaaattagcca ggcatggtgg tgggcccctg 112620 taatcccagc tactcggaag gctgaggcaggagaatcgct tgaacccaag aggcagaggt 112680 tgcagtgagc cgaaatggca ccactgcactccaccctggg tgacagaagg agatttcatt 112740 tcaaaaaaac aaacaaacat accgtaaatgtcaagaaatt tacatttttg catggtctta 112800 ttatctcccc acaagataat tactaattacaaaaggacac ttattataaa attataaaag 112860 agaaacccag cagataacct ctttaaccacatgatcagtg ttaacatgcc cagtaataag 112920 tcatatcaac agaaagtagc ccctgatctgatgcactaag aagggcataa cgttacttct 112980 gtgatattct tgccaaaagt gcataagctcaatctaatca ccaaaaaaaa aatcagacat 113040 tcaaattgag ggatattcta taaaatgactgaacagtacg tgtcagggtc atttgagaaa 113100 aaaagcgaga ggctgaggag ctgtcatagattagagaaga ctaagaagac attacaacta 113160 aatgcaatgt tggaccttgg attagatcaaaaggaaaaca gctaaaattc aaataaggta 113220 tgtaggttac tgtaccagtg ttaatttcctggttctgata attgtactaa ggtgaggtaa 113280 gatgttccta tcagggaaag ctaggtgaaggtgtaggaaa tgaagagttt aggataactc 113340 tgaactattt ttgcaacgtt tctgtaagtctaaaattatt tcaaaattaa acaccaaaat 113400 aactataaaa tataatttat atatgaattatatctaaatt ttgaaaacta tagctaggtg 113460 tggtggtgtg cacctgtagt cccagctactctggaggctg gggctggagg gccgcttgag 113520 cccaggagtt caaggctgca atgagctatgatcgcactgc actccagtct gggagggaga 113580 gcgagacaca ccatctgtaa aaataaaaaacctatgaaat cttgacaaag tgagacattc 113640 atatttaatt ctttcggatg ctatcttctccattaccagg gatcatcttt cttttctaat 113700 gtgaggtggc atttagaatc tctgtacgttccagatgatt ctcggcttca agacccagct 113760 cgaatgccac ctcttccaag aagctctgactgatcaccac agttgcacag ctagaaattg 113820 tgtcttcatc ccctaaatgc ccatgacattttttgtgcgc atctattagg gcatttatca 113880 tctccatagt ggacatctat ggtattctcttcccagctca cctgcccagt tctgcttctt 113940 cctcttctga ctccaaccat gccgttctcatgggagctgc catgttgtta cagaccccac 114000 agctgattgg tccagagata gacatctgacccagctgggc caatcagaca ccttccctgt 114060 ttttgtggca gttgctttct tttttctttctcactgaaac tgagttaagt ttaacctaaa 114120 gcttcttcct tacctgttgt atattaatttgggtctaaag gtttctccat acattgtgaa 114180 ctgtaatcta attaggtatg taaacagaccgtaaggtact cttgtaacaa gtggctaggt 114240 ctcatccagt cacagctgct gagtttcagccaattgcagg ccgaccacag ttcaaacagt 114300 gtaccaataa tgccaaccgt aaccaatctagctgtttctg taccccactt ctgttttctg 114360 tatgtaactt tcctttttct gtccataaatgtaatctgac ccttgtggca gtctctgagt 114420 tgctgtgaac ctatcctggt tctgcaaggctctggatttg tgaattgctc tttctgcagt 114480 tacactttgt taaatttaat ttgcctaaagtgcccccccc tccaccgcca attagaggta 114540 gggactcgct atgttgccca gactggactcaaactcctgg gctcaagcga tcctcccacc 114600 tcagcctccc aagtagctgg gactacaggctcgtgccacc gtacctagtt cagagttttt 114660 ctggtaacat tagccaccat gttctctgccacatggagga accctgtctg taactagagt 114720 gagaagacag ctaaggcaga gagagaagcagagacacaga atgaggagag agagagagaa 114780 gagagagaga gagtgcatgc aaatgggctgattccacctg ttcttgaagt tttctgtcct 114840 tgccaagagt ggttgtttgg ttgatccctagtcactacat aaccctcaga atccaaaaaa 114900 tcttctggta aaaccctctt ccaataaatcttttttttta aattaagtaa ttagaagagt 114960 tttatgtggt tctcatccca agttgcaatgagctactctg agttatttgc atacatgttt 115020 tctctctcct actcatctga gggttgccaaatgcccatct tagatacagt tctcactggc 115080 ccaaggctag tgagaaaact aggacaacatagtgagtcac ttacataggt aatttttaaa 115140 attgccaaat tctgggatta gtccttgttattgaatttta tgagatgatg gtaacagcag 115200 aaagtagcaa tttatttttc cttttaatattctttgacaa ataacaagat gttggcaatt 115260 gtgtacccca atttaggaaa aaactttactgggacatgaa atcccagtga agtgctggcc 115320 aggtaatgat tcctctgggt ggggccccctcttggctctc agcagagagc cttgtaaatg 115380 agtgagatga gctaatggct gtagggagctgttctggtct cctgtgtctt gtaggaatac 115440 gatctgattt agaacagtta cagcttattcattcccccag ttcttttacg atttttcaag 115500 gaggcttact ttttattttt atttttttacttatttgcaa aataccctat tagtcctgca 115560 gggcccttcc tttcaaattg atctcatgttgattttctct ttaatcctaa tcacctgtgt 115620 aggtgtgaga gttgaggtga agtctcccatctgggaaggt tgaggggtcg agggtcagct 115680 cgctgtggtg gggaaacagc actggggtgggagtcagaca gcactgttgt ccacctatgg 115740 tttctcctct tgctggttgc aaggcctcaagcaacttgct tcatttctct gagcctcagt 115800 ttccccgtct gtgacatggg gatgatatctagcctacctt ttgcacaggg ctgttgcaaa 115860 gggttgaata aggctttggt ggcaatttggagctgaagga ggcagcaggg gatgggacag 115920 gtgcccagtg ttgttttata gaagctgctaggggccgggt gtggtggttc atgcctgtaa 115980 tcccagcact ttgggaagct gaggcgggtggatcacttga ggtcaggagt tccagaccag 116040 cccggccaac atggtgaaac cccgtctctactaaaaatac aaaaattagc ccggtgtggt 116100 tgcatccgcc tgtaattcca gctactcaggaggctgaggt agaagaatca cttgaacctg 116160 ggaggtggag gctacagtga gccaagatcacaccactgca ctccagcctg agcgacagag 116220 caagactcca tcacaaaaaa taaaaataaaaataaaaata gaagctgata gggtatatct 116280 gagggggaaa agattcaata acagaaattgaaatgtaggt aagcgtgagg aagttgtaag 116340 cacttcctag ctctgtcttt tttttttttttttttgagac ggagtttcac tcttgttgcc 116400 cagggtaaag tgcagtggcg tgatctcggctcacggcaac ctccaccttc tggggtcaag 116460 cgattctcct gcctcagcct cccgagtagatgggatccac ttcccaggtt caagcgattc 116520 tcctgcctcg gcctcccgag tagctgggattacaggcatg cgccaccatg cccagctaat 116580 tttgtacttt tagtagagac agggtttctccatgttgatc aggctggtct cgaactcgcg 116640 agctcaggtg atccacccac ctcagcctcccaaagtgctg ggattacagg tgtgagccac 116700 tgcacccggt ctctagctct gtctcttacttgaatgtgat ctcaccctgt gtgactcagc 116760 ttcctcattt ggaaatccag gtctcacagtcaggaagtaa ctttttggat accttacact 116820 gaacactgaa ggttgcataa gagttggttacaggctgggt gcagtggctc atgcctgtaa 116880 tcctagcact ttgggaggct gaagtaggtggctcatctga agacaggagt ttgagaccag 116940 cctggccaac atggcgaaac cccgactctattaaaaatac aaaaattagc caggtgtggt 117000 ggcacttgcc tgtaatccca gctactcgggaggttgaggc aggagaatct ctggaacccg 117060 ggaggcagag gctgcagtga gcaaagattgcaccactgca ctccagctgg agacagagca 117120 agactccgtc tcaaaaaaaa aagagatacactccaggtag atgggactgc atgagcagcg 117180 gcttgggtta gaaattacgg cagcatggatgagagacacc gttctcatgt attttgtttc 117240 aggaggacaa taataatact tgtttattgtgatgacaatt aaataagata atgcaggtaa 117300 ggtgcttagc agaggcttgt acataaccaactcagtaatg gtgcttgttt ttaccgccat 117360 ttttgttgtt gtttttacaa ataaagaaaacaaaggctct gataggtgat atgtaggcca 117420 ggcacacagc tattggttgt tgagcaggatttgaacccac agcttttatt tatttattta 117480 cttatttatt tacattttta aatttaatttaattaatttt ttttttgaga tagggtctca 117540 ctcattgccc aggctgcagt gcagtgatgtgatctcagct cactgcaacc tctgcctccc 117600 gggttcaagt gattctcctg ccttagcctcctgagtagct gggaccacag gcacatgaca 117660 tcatgaccag ctaattttta tattcttagtaaagacaggg tttcgccata tcggccaggc 117720 tggtcttgaa ctcctgacct caagtgatccgcctgccttg gcctcctaaa gtgctgggat 117780 tacaggcgtg agcccactgc gcacagcctatttatttact tttagagaca gagtctcact 117840 atgttgtcta gggtggaatg cagtggctattcacagtcac aatcccacca ctgatcagca 117900 cagttttgac ctgctccatt ttcatcttgggcctgttcac ccctccttag acacccctgc 117960 ttacaggagg tcaccatatt gaagctgaacttagcacaga cactcgatca atatagtaca 118020 ctacagccta gaactcttgg gctcaagaatccctaggctt atcctcctgc ctcagccttc 118080 cgaggagcgc gaaccacagg gacacaccactgttcccagc accatatctt cttgacagag 118140 accaggctct gaaccactgt gttcaagttaccccactgtg gggcctctgt tcctgcccta 118200 ggggcctccc tgactcagca actgtgggtggccttgcttc tgtgcctgga cagcagagga 118260 ggtgagaagc cttccagtgc cttgaaaactaaatacggcc aggccaggcc tctgaggccc 118320 gaccctcagg cttggcctgc tcctgcctgctcatatgggc tgtggggcgc tactccctac 118380 tcaacttcct ggctctgctc cagggggctctggcagaacc tccatccaga tcctccttct 118440 caggatcttg ttgggaaaaa tactaaaagagaacataaaa tgaatgcctc ttatccatgc 118500 tgcaataatt cctaattcta agactttgctcaagtaattt ggtccatgga gtacctctct 118560 aatcagtgct taatgtgtct ttggtggccagtgtgagcta tcaggaagag ttactttata 118620 actgtgagac ctgcagtaag tcactcatctcatccatcca cccatccatc catccatcca 118680 tctacccacc cattgggcac ctacctgtgccaaacacatt acatacagac tcttcttcca 118740 gaccggaaac tccatgagaa ttgcagaccaggtgtcaaaa gataattatt cagggcaggc 118800 atggtggctc acgcctgtaa tcccagctctttgggaggcc gaggtgggcg gatcacttga 118860 ggtcaggagt ttgagaccag cctggccaacatggtgaaac cctgcctcta ctagtaatgc 118920 aaaaattagc caggcatggt ggcatgcatctgtaatccca gccacttggg aggctgagac 118980 agaggaatca cttgaatcca ggaggtagaggttgcagtga gccaagatcg tgccattgca 119040 ctccagtcta ggcaacagag taagactctgtctcaaaaaa aaaaaaagaa aaaagaaaga 119100 taattattca accaatatcc atgtgtctcaatgtgtctcc tccaatttat atattgaaac 119160 gtaatctgca atgtggtagt attaagaggtgggacttttg ggggcgatca cttcatgaag 119220 ctccatcctt ataaatggga ttagtgcccttataaaagaa gcctgaggga gtttgttcac 119280 cccttctacc atgtaaagac atagaagacgtcatctatga ggaacaggcc ctcattgaca 119340 cccaatctac tgacaccttg ttcttggatttctcagcctc tagaactatg agcaacatat 119400 ttctgttgtt tatatattac tgagtctgaggtattttgtt ataacaacag gagcagacta 119460 agacaatgaa ccaatgggcc aaggcttgtccttactacag tcctggtaag gctgttatca 119520 ttatcacccc catttcacag ttgagaagcccgacactcag agaggggaag tacaaagaac 119580 atacagccag agatgagtgg agctgagacttggccaagtt cttaaccctc ctaacaaagg 119640 gaggaaccat gctgaggggc aggccctggaggaggacacg gaccatttct ccttcagctc 119700 ttggcttcct tggtgggaag tggattaattctttctcttg tctccctcct aaccaagcct 119760 ttgagggtgc ccagctcaga gtctacaaagtccttttcaa ggtttccaga gccctcctct 119820 cagccctgta ggggattcag ggcggggggaccttccccat ggttcagatg ggagaattga 119880 ggcctctgta ctgcccacag tcacatgccatattaggggc ctggaatctc atgcttcaag 119940 aaactgagca tggaactggc tgctagatatttcctgtagg tgtggtatga agcgcttaga 120000 gtctgacagg tcctagctct gccacttacaagttatgcag tcttagagga atcacttcac 120060 ccctctgaac cgcagacttc tcccctgaatagtgaggaca gtgctagtac ctatttgaga 120120 gatgttggga ggatgaaatg aaagaatgcttgtgaagcac ttagcgtagt acctggaaca 120180 tagtgagtgc tccaacaatg aggttatgatggtacgaagt acctaaaaca gaacatcaga 120240 ctggtaggag tatccatgct gagggtaatattagctaatg tttctctttt tttgagacag 120300 aatctcgctc tgtcacccag gctggagtgcaatggcctga tctcggctca cttcaacctc 120360 cacttcccag gttcaagcaa ttctcctgcctcagcctccc atgtagctgg gattacaggc 120420 acaagccact atgcccagct aatttttgtatttttagtag agacagggtt tcactgtgtt 120480 ggccaggctg gtctccaact cctggcctcaagtgatccgc cctccttggc ctcccaaatt 120540 gttaggatta caggcgtgag ccaccatgcctggccagcta atgtcttttt tattgctact 120600 atgtaccaga cacagtcatc tggacaatatccctctaact tagtgccatt ttacagatgt 120660 gataactaag gcttgaaatt gacttgccctagctccttgc ccagcaagag gaagagtctg 120720 ggcctgaacc tgagtctaag tccatgatctcaggagctct gatccactgt cttggattct 120780 ccaactccat tatgttgaag ccaagagaggaaaagggagt ttctcagggc accatggaag 120840 gtgggggtag ggcagaccac actggggaggaattttttct tcctggcagc tcttcatggg 120900 tctggataat tctccagctt taggattaaggcagagcctg actagcacat tcatagtcct 120960 ctggaaggat ccagggatct ggcttttagtctcaggccag ctagcagatt ccatttccac 121020 tcccccgacc cgagctttaa tgacaccttcagcccctact ctactctgtg actgcccgtt 121080 ccccaccccc agctttaatg catgggggccccctttttta atcggctgaa cctttagcca 121140 aagaaaactc tttggtgccc gcaaaaccagccagctgccc tggaatgttg gaggggggtc 121200 atcaagctgt ttgtgagctg ctggcagagaaaggtgaaca gctacctttt tggggggaaa 121260 gtcagaacat catctgtggg aaaagatctagggcagacca gctcagaggc ttgggcctca 121320 gtttcccata ttcaccacca tggcatgtatgggggatgaa taacttcagc taaagattca 121380 agaactattg tttgggtgct tgctacatgccaggtactgc actggctgct gcagacacat 121440 cggggacaga gttaagccct gtccttgggggctgacattc tagcagaagg cagtcgctca 121500 gtaagtttcc caacaggcta gaggcaggtgcctcaggccc ataagacctg atcaacacac 121560 ttgtggctgg ataggtttca gaattcatttttgttttttt cagccagggt ctcggtctgt 121620 tattcaggct ggagtgcagt ggcacagtcatggctcactg caacctcaaa ctcctgggct 121680 caagtgatcc tcccgcctcg gcctcccaaagtgctgggat tacaggcatg agccactgct 121740 cccagcctca gaattcagga tttttttagattttaaaagg taatccagtg gggtctggat 121800 ccatccatct ccaatgaaac atacgaatatttctgtagct agaagtgtga gtattgactc 121860 taagtgaaat gaacagattg cacaccctcagtcaatccag gtcagatatt gctcctgaat 121920 gagttttcac taagtgtgca gaaaagcctctggctgtctg aattttctga acttggagct 121980 gtaggtatga gattgagggc ctgattcctcttcccattgt acagataaga aaactgagac 122040 tcgggaccag agagtcacct acccaaggctcctgagcgag caaaacctgc aggtgggtgg 122100 gaatgcaggt ctactgtggc tccagattgacggcttgcca ctaacaggga ctgtgcctca 122160 gagagaagca gggacgggtg gagaaggctccttgaccaaa ccttagcggc ccagcagcca 122220 gttctgccag gaaggagtta aacactagctgggcccctgc caggcctctg caccacggct 122280 cctcacaggg cctgcctgtc tggggcctgtttaccaggct gtgcttgcat caccggctct 122340 ggctccgacg tgcagtgcaa acacattcacattcttgggt catgagaaac gcacaattgt 122400 ggtgacatca tgcccagcga ggaggctttcgacagcctct ttcccgcccc aagtcaaagc 122460 tgtttaatta gctcccttta actggaactctctcttctcg taaaaaccaa ctggagatac 122520 tgaccaagtg cgggtgatgg ggattggagtgttgtgtgtt tctgtgtgtg tgtgttttaa 122580 gggataaaaa tagcccatct gggactccttttggggtatt tgtgagtgtt aatgcacgag 122640 tgtttatatt aaatctatgt cacactggacattttcatcc aaatttgggg cttggagatg 122700 gaacaaggga aaccacccac atcttttggttccctctagt ttttcctttt gggagggaga 122760 cacatggtcc aagtaaaagg gccctgggagacaatttaga tcaatccctc attatacagc 122820 caaggaaaag gaggcccaga gaggggagggccttgcctga ggtcacgcag tgaggctccc 122880 agttcccata cccctgggat gtatcttgtggcacgcccct cagcccccat ttcagcttta 122940 tgagctgttt ttcagggtgt tggaaagagaagtgctcctg gctagagctt cctggctatg 123000 ttttgagatg aagagtgaac ataccagcttgggcaacata gggagacccc gtctctacaa 123060 aaattttgta aacattagct gggcatggtagtgcgtgccc atggtcccgg ctactcagga 123120 ggctgaggta ggaagatcac ctgagtttgcgaggttgacg ctgcagtgag ctgtgattgg 123180 ttattgcact ccagcctggg agacagagtgagatcccatc tccaaaaaaa aaaaaaaaaa 123240 aaaatgtggg gcggtggggc caagcacagtggctcacacg agtaatccca gctctttggg 123300 aggctgaggc aggcggatca cttgaggtcaggagtttgag accagcctgg cagcctggcc 123360 aacatggtga aaccccatct ctattaaaaatacaaaaatt agctggatgt ggtggcgggc 123420 ccctgtaatc ccagctactc aggaggctgaggcaggggaa ttgcttgaac tctggaggta 123480 gaggttgccg tgagccgaga tggcgccactgcactccagc ctgggtgaca gagcaagaca 123540 gtctcaaaag aaaaaaactg tggatacctttttttgtggt ggtggtggtg gtggcttcca 123600 catgtggtgt tggggtggca gcagtgaataataaaacaag agacctcagc ctccccaatc 123660 tcctgtcttt ctttttttga gacagggtattgctctgttg ctcaggctgg agtgcagtgc 123720 tgtgatcaca gcccactgca gccttgacctcccaggctca ggtgatgctc ccacctcagc 123780 ctccagagta gctgggacta taggcatgtgccatcacact cagctagttt ttgtggtttt 123840 agttcagaca gggttttgcc acattgcccaggctggtctc gaactcctgg actcaagtga 123900 tctgcccatc tcggcctccc aaagtgttgggattacaggc ctgagcaact gtgcctggcc 123960 acctcctctt tttctgtccc aacgacttgcctctcccccg cagatcaccc caggtcttct 124020 tttgtttctc tttccaaaga agtcccagtccttgctgact tcctgcgatg gccactgaag 124080 cttgtttctc acttagggat actaaattgagccaatataa atgtaggaca cccagttgaa 124140 tttgagttca gataaacaac gttttagtttatgtcccacg gaatatcagg atatacattt 124200 atcgagcaac cctattttct tcctcctgcatcatcctggc tgtggcagat actcttgact 124260 gcctccccat taaccttcct tctacttccttgataactga gccctgattt ctgtctgtgg 124320 tggcagtgtg tcccagttgg cgaactgtgattggtctagg ctagtcatga caatcctgtt 124380 ctctgttgtt ttccctgact cccttgtagtgagaaatgat ctgatggtta ttattattat 124440 tatttttttt agagacaggg tctcactctgttgcccaggc tggagtgcag tgacgtgatc 124500 atagctcatg gcagccttga acttgtggctgagatcctcc catctcagcc tccccagtag 124560 ctgagacaac aggtgcatgt caccacacctggctaatttt ttaaaaaatt tgtagagatg 124620 ggatctcact atgttgccca ggctggtctcaaattcctag cctcaagtaa tccccctgcc 124680 ttggcctctc aaagtgctag gattacaggcatgagccact gggcccagca gatctgatgg 124740 ttttaagata tgcctgcaag ttccttgacatctctccttt cagaaggtgg agactcatcc 124800 cttccccttg aaagtaggct ggacttagtgattcatttca aagagtgatt tctgagggca 124860 gctcataaaa accattgttg cttctgccttgctctcttaa attactcatt ctagcggaag 124920 cctgctgcca tgttgtgagg acacccagtagccctatgga gaggcctgca tggggagaac 124980 ctaagtcctc ccatcaacag ctagccccagcttgccaggc atgtgagtga gcaaccttaa 125040 aagtggctcc agacccagtc aagcctttgaatgactgcag tgtgggccaa cattctgaca 125100 acagcataaa ccagagatat gcctgtattaatcatatttt tcattttctt tcttcttttt 125160 ctttcttttt tctttctctt tttttctttcttcctctcct tctctttctt tcttctttct 125220 ttcctctttc tttctctttc tttccctccctcccttcctt ccttccttcc ctttctttct 125280 tcctctcttt ctttctttct ctttctttctttttcttttt cttttgtttt ttttttgaga 125340 tggagtctca ctctgttgcc taggctggagtgcagtgaca caatcttggc tcactgcaac 125400 ctctgcctcc cgggttcagg cgattctcctgcctcagcct cccaagtagc tgggattacc 125460 ggcacgctca accatgccca gctaatttttgtatttttag tagagatggg gtttcaccat 125520 gttggtcagg ctggtctcga actcctgaccttgtgatctg cctgcctcag cctcccaaag 125580 tgttgggatt acaggcgtga gccaccgtgcacagcttctt tttttttttt tttttttttt 125640 tttttttaaa gagacagggt cttggtctgttgcccagcct ggagtgcagt agcatgatca 125700 tggttcactg cagcctggaa ctctggggctcaagtgatcc tcctgtcagc ctcctgcgta 125760 gctgggacta taggcatgca cctccatgcctggctaattt tttttttttt tttttttttg 125820 agacagagtc tcgctctgtt acccagtttgcagtgcagta gcacagtctc ggctcactgc 125880 aacctccacc tcccgggttt aggtgattcttgtgcctcag cctcccaagt agctggaatt 125940 acagacatac accattaggc ctggctaatttttgtatttt tagtagaaat ggggtttcgc 126000 catgttggcc aggctggttt cgaactcccaacctcaggtg atctgcccgc ctcagcctcc 126060 caaagtgctg ggattacagg cgtgagcacccaccctcatg cctggctaat ttaaaaacat 126120 ttttcttttt ttttttgagg ccgtgttttcgctcttgtca cccagacttg tgccagtggc 126180 atggtctcag ctcattacaa tctccacctctgggtccaag caattctcct gcctcagcct 126240 cctaagtagc tgggattaca ggcacccgccaccatgcccg ataatttttt tttttttttt 126300 tgagacagag tctcgctgtg ttgccagtggcgtgatttcg gctcactgca acctctgcct 126360 cccaggttca agcaattctc gtgcctcagcctcccaagtt gctgggacta caggcgtgtg 126420 ccaccacacc cagctaattt ttgtatttttagtagagaca gtgtttcacc atgttggcca 126480 ggatggtctt gatcttctga cctcgtgatccacccgcctt ggcctcccaa agtgctggga 126540 ttacaggcgt gagccactgc acatggcctaaaaatttttt tgtagagatg ggggtctcct 126600 tatgttgtcc agactggtct tgaactcccaggctcaagtg atcttcctgc cttgacctcc 126660 cagagtgctg ggattagagg tgtgagccactgccccccac catttttcat tttcttggag 126720 tttgtgtgtt tccatgtgtg tgtgtatatgttttaaggga taaaaatagc ccatctggga 126780 ctccttttgg ggtgtattaa tgcaccattgtttatattaa atctatgtca aactggacat 126840 tttctcatat tttatgttgt ttttgacatatttaagggag ggcttgccgg ctggaaagag 126900 acttctgctt ttagggctag gtaatttctagagacagtga acaacttgtc agtgagccca 126960 ccttttatac acaaaccagt gaatttcaagtccatatcct cagcctcctt tatccaattc 127020 tcatacaccc tgccctaaat caatctagggccaggtaccg ggcaactagg aacagcccct 127080 attccccaaa gctctctgga atgattcgaactaggcagtc ctaaactgtt taccacaccc 127140 tgccttgcct tcctgtggaa aacaaaataaacctgtggct atgccttctc cttactcctt 127200 tctgcctctc gactgactga cgctagtgcttctccctgtg gccccgcctg gcatgctata 127260 cctctgattt ttagggaact gtaagtcacgtaaaactttt ctttcaatgg cattgacctc 127320 tctgtgttgt cacttagtca cctttataaattaaaacctg ggcacaggct aggcacagtg 127380 gctcacgcct gtaatcccag cactttgggaggccgaggca ggcggatcac ctgaggtctg 127440 gagtttgaaa ccagcctggc caacatggtgaaacctcatc tctactaaaa atacaaaaat 127500 tagctgggtg tggtggcgca cacctgtagtcgcagctact ccggaggctg aggcaggaga 127560 atcacttaaa cctgggaggt ggaggttgtaccaagcggag atcgtggaga cagagcaggc 127620 ccctgtctca aaaaaacaaa acaaaacaaaaccccaaaaa acaaaaaaac ctgggcagaa 127680 atcaactcag agattctgag ccagaactacctaattaagc cattcccaat acctgaccca 127740 cagaaagtct gagatagtaa tcccagcctcccaaaatgct gggattacag gcatgagcca 127800 ttgcacaaag tcagaatgta gcaattctaagataccctac agcacattta ttctgttatc 127860 tctgtacttc acagatggga atctaaggcccaagggtggg gaaggcacag cctagaatag 127920 tacaggagac cagtggcaga gtggagattagaatccagaa ctttgaactt tccctttctc 127980 caggctgtga ggaaggcagt gtggattcccttggaccacc caaacatttc ctttcaggag 128040 gaggcgattc ttgacccagt gctgctaccagctccccctg ggtcaggaag ctctgcctgc 128100 ccaggatttc ctgtgtgtgg gaaagaaacaggatgagtag ataaatcccc caaggctttt 128160 tttccccaag tgcgtgaggt cctctccctggtaagtctgc agcagttcta gccaagatga 128220 ccaacccatc gacatgtatt ttgtgtgtttataaacagta ataaaaagaa tgattggcaa 128280 ggcacagtgg ctctcacctg tgacctcagtattttggaag gccaaggtgg gctgatcgct 128340 tgagcccagg agtttgagac cagtgtgggcaacacagtga gaccccatct ctacaaaaaa 128400 ttagccaggt atggtggcac acgcctgtagtcccaggtac ttgaaaggcc gagatgggag 128460 gattgcttta gcccaggaag ttgaggcttcagtgagccga gatcacacca ctgcactcca 128520 gcctggacaa cagagcgaga ccctgtctcaaaaaaaaaaa aaaaaaaaaa agaacgattg 128580 catgtgcatg aagcacaaga caggaggtaggggagaagag tccacatcac cgtcccttgt 128640 ccctgccctt gtggagctgc ctttgtttgggtcctcccag aagcaggtct taagagaagt 128700 atttaagttc aagtaatctg tctgggaggtgatcccaggg aatcccctgc aggggagtgg 128760 ggaggtgaga tggggaaagg aaagcagccaataaattcaa taaatgaatt gaaagcacac 128820 ttcgataggc aactggagtt caaccccactagggaaagct cagagacagt catcccaacc 128880 aaggagcaag aggcagctgg agtatctagccaccaacttc tcattcttca ctggttgagg 128940 gatgcttctg gaactcagcc ttcccgcttgccagaggaca ggcccaagtg tgctcctgag 129000 gtcagaacaa cacagtcaag cagttacattcacagtaaga agcctttgat gggtagaggt 129060 atcatcaggg gcctctgggc ggtatctgctccagaggctg accactaatg agttttccat 129120 ccacaggaaa aggcagaagg aggcccaggagacatgcctt cccctccctg ggtggggtta 129180 tggaggccgt gtggagtgca tagtgggccttttgcctgtt caggccccca tcaccccttt 129240 cttctcattt tgaggaatca ccttaccccactgtggtcca catcgtcctc ttcaacactg 129300 tactagacca catttcccag cctcccttgctgttagggga gccatgtgac tgattccagc 129360 caatgaaatg tgagcagaag ggacatgtgctgttttcaga cttggtccat aaataccaac 129420 cactcacttc ctttcgcttt ttctctctttttaacttttt tggagacagg gtcccactct 129480 gttacccagg ctggagtgca gtggcgtgatcatggctcac tgcagccttc acctcctggg 129540 ctcaagtgat catcccaggt tcaagcaatcctccagcctc agcctcttga gtagctagga 129600 caacaggtat acaccaccac acctggctaatttttttatt ctttattttt tttgtagaga 129660 caaggtccca ctatgtttct taggctggtctcgaactcct gtgctccagc aatcctcctg 129720 ccttggcctt ccaaatagct gtgattataagtgtgagcca ctgtgcctgt ctcgcttttt 129780 ggaatgtctt caatggtgct ttggaggaagaaaacatcat gtgaatgact acacaaatca 129840 ctattgtcag ttgggagtta gctctgagaggaaaagttta gggtgtcttg agcactttga 129900 cttgagatcc agcagaggaa gtcatgggcaaaggccctga agcaggaagg aggagtctga 129960 agtgggccat ggtgactgga ggttatgaacaaagctgaat ggcctgagag gaaggcacat 130020 gatcttgatg taaaactcat aggtgtgtgtattagtctgt tttcacgctg ctgataaaga 130080 cataccaaga ctgggaataa aaagaggtttaattggactt acagttccac atggctgggg 130140 aggcctcaca atcatggcgg aaggcaaaaggcacttcata catggtggcg gcaagaggga 130200 tgaggaagaa gcaaaagcag aaacccctgataaacccatc agatctcatg agacttattc 130260 actatcacga gaatagcatg ggaaagaccggcccccatga ttcaattacc tccccctggg 130320 tccctcccac aacacatggg aattctgggagatacaattc aagttgagat ttgggcgggg 130380 acacagccaa accatatcag tgtgtgaggagttagatgga tatgggctgg acactgccct 130440 ggcacccttc ttcctctttc tggggacagagagccagttt gagaaaccag attataacca 130500 ggaggggctg agcctagaaa ttcaacagaatttgggcata catgtggctt gcagagacat 130560 ggaattcagt ggttcccatg cctggagccccctgctctgg tctatagtgg cagaagggct 130620 tttctgtctt ccagacacag ctcagtctcacctcattctc aggtcatgtg gcctgaattt 130680 gatgggtttt caaatcatgt gccccgaccatcttgtgtat gggctgggta cctctcatcc 130740 tacacaaatg actttccagg tcaggtgctgtggctcacac ctgtaatccc agcactttgg 130800 gaggccgaga cggggagatc acctaaactgggagttcagg atcggcctgg ccaacatggc 130860 gaaaccctgt ctctactaaa agtacaaaaatttagctggg catggtagtg caaacctgta 130920 attccagcta cttgggaggc taaggctatgagaatcgcat gaaacgggag gcagaggggg 130980 ttcaagtgat cacacagcga gccgagatcgtgcaactgta ctccagcttg ggcgacagag 131040 ggagactctg tctcaaaaca aacaaacaaacaaacaaaca aaacaaatga ctttccaaca 131100 tcagtgcaat aggctcttct tgaggactagcctgggagcc ttgctccttg gtgttgtgaa 131160 acctcaagta actgatttaa tattgaactgctgggccaga gctgcaagcc tgacctcagg 131220 ggctgccttt ctcctgcccc accccctcccctggagcagt gtcctctggg gaaatgcagc 131280 tgacccagct gcatccgtgg gaaggcctggcccccacact tcaccttctc agccctgcct 131340 ctcggccaca ggaaatgacc ctcttagcagccacgagctg tgatccagag gacaatgaca 131400 gagggacgga agccctgttt gtcccagctaacttgttccc ttgggtggat gccagctgct 131460 gaaacaaaaa actgaagatt cagtggaaaacatatttttt acaaaacaaa caaacaaccc 131520 tgtgggcttt agccaacttc tgaggctctggggccggggg agggggggtt gttttcttta 131580 cttgcttctg tgtgtgtgtt taaaacacagataaagctca gagaatcaaa tagcctaaag 131640 cttggaagaa ggccagtgat cccaccctagcagcagagcc cccctgtggt gtctttcttc 131700 atgtggctgg gccccacttc tccacaccactgttcatcat gtcacttggc tccggccact 131760 gcccccaccc cacctccatt caccacccagaagtcagaaa gctctgctca aacccacatc 131820 aagtcaccat tctagggctc tgcaggctgcctgtctcagt cttcaagtct ccagctcaaa 131880 tgccacctcc tccaaggggc ttccctgaccattccatatg aaatagcacc tctcagtctc 131940 tctccctccc atagcacttg taactcttactatatctgga atgatctgct ttgtttccac 132000 gtgccaggca cgtagtagct actcaataaatgttggttga ctggcaatgt ttctcagtgg 132060 ttgttgcatt cagatgaaaa ctggcttagaaaatccatat tccattgtat ttcaacaaac 132120 attattggcc acaaacagtg ctagggatcagaggcaaatt agttgggatt cgttcattca 132180 ctcactcact cattcattca tgagaagggtagaccccatg gtaaatgggg attcagccgg 132240 gggtgcagag aaccaggaaa gctttaggtgggaggagatt gttggtgggt ttccccccat 132300 taaagtaggg ttcagaggtg tgagcaagaaagtgtttgga aaaacaagag aaccttgggg 132360 tgtggaattt aatttattcc cacttagaacccccagggag ggcagagacc cgattttatc 132420 tggggctgca gagagggcac tctccatgtgcttgttgaag gaactgaggg atgagggatg 132480 gtcaggtagt gtatgaagtt tatggctctgtttaagaggt tgctgtgacg tcccgaatgc 132540 caggctatga agcctggatt tccatctatagggaacagag tctaatcaaa ataatgattt 132600 tggtgctggg tgtggtgact catgcctgtaatcctaacat tttgggaggc tgaggcggga 132660 ggatcgcttg agctcaggag ttcaagatcagcctggagaa catagtgaga tggagtcgct 132720 aattaaaaaa aaaaaaaatt agccaggcatggtggtgcgt gcctgtagtc ctaactactg 132780 gggagactga ggcaggatga ccacttgagcctgggaggtt gaggctgtaa agaggtgtga 132840 ttgagccact gcactccagc ctgggtgacaaagcgagacc ctgtttcaaa aaaaaaaacc 132900 ggctgccacg cacggtggct tacacctgtaatcttagtac tttgggaggt cgaggcaggt 132960 ggatcacctg agttcaggag ttcaagaccagcctgggcaa cacagtgaaa ccctgtctct 133020 actaaaaata caaaaattgg ctgggcgtggtggtgtgtcc ctgtagtccc agctacttgg 133080 gaggctgagg taggagaatc acttgaacctgggaggtgga ggttgcagtg agccgagatt 133140 gtgcccctca ctccagcctg ggggacagagcaagactccg tctcaaaaat aataataatt 133200 ataaaataat aatgatttgc aaagcctgtttgaagtgcct gaatgtcact gattcctgaa 133260 ctccagttct ctagctacat cagagtatccaaaccccatc ctagaagagt ctgattcacc 133320 gtaagttgga gtcggggcct ggccatctgccattttcaca cacttgccag atgtcgttgc 133380 tattcactag gtttggtgac cactgaggctcagagaggtg aaggcacttg cccaaagtct 133440 gtaggtggtg ggggaggggg cggaggctggtgtttgaacc tggttggcct ggccctccac 133500 attcaccagc tccacttcgg cctcccgctggactggctcc tttctccatg ttattttccc 133560 ctggatgcag gaatctgggc tgtggctgagcctgcccgcc ctgtcctctc ttcccatccc 133620 cgcccccagc ctcaaaggtc aggtacctcccagcctccct cggtcgtgtc catttatggc 133680 tctgttgttc caaaatgtgg ccaaatttataaactcccct ttcctggaga cacgaaacaa 133740 tttgtgcaga gtgcagtgcg ggggcagagctgggagcttc atctaagacc tggacttcag 133800 cccaggccca atgagctctg gcgttgaacaggctccagtt cctccctggg cctcagtctc 133860 ctcacctgca gagtaaatat actggactagatc 133893 2 2230 DNA Homo sapiens 2 gagccaaggg agtccaggct gccgggggctgcagacatgg agggccagag cagcaggggc 60 agcaggaggc cagggacccg ggctggcctgggttccctgc ccatgcccca gggtgttgcc 120 caaactgggg caccctccaa ggtggactcaagttttcagc tcccagcaaa gaagaacgca 180 gccctaggac cctcggaacc aaggatcactgtggtcacat ggaacgtggg cactgccatg 240 cccccagacg atgtcacatc cctcctccacctgggcggtg gtgacgacag cgacggcgca 300 gacatgatcg ccatagggtt gcaggaagtgaactccatgc tcaacaagcg actcaaggac 360 gccctcttca cggaccagtg gagtgagctgttcatggatg cgctagggcc cttcaacttc 420 gtgctggtga gttcggtgag gatgcagggtgtcatcctgc tgctgttcgc caagtactac 480 cacctgccct tcctgcgaga cgtgcagaccgactgcacgc gcactggcct gggcggctac 540 tggggtaaca agggtggcgt gagcgtgcgcctggcggcct tcgggcacat gctctgcttc 600 ctgaactgcc acttgcctgc gcatatggacaaggcggagc agcgcaaaga caacttccag 660 accatcctca gcctccagca gttccaagggccgggcgcac agggcatcct ggatcatgac 720 ctcgtgttct ggttcgggga cctgaacttccgcattgaga gctatgacct gcactttgtc 780 aagtttgcca tcgacagtga ccagctccatcagctctggg agaaggacca gctcaacatg 840 gccaagaaca cctggcccat tctgaagggctttcaggagg ggcccctcaa cttcgctccc 900 accttcaagt ttgatgtggg taccaacaaatacgatacca gtgccaagaa acggaagcca 960 gcttggacag accgtatcct atggaaggtcaaggctccag gtgggggtcc cagcccctca 1020 ggacggaaga gccaccgact ccaggtgacgcagcacagct accgcagcca catggaatac 1080 acagtcagcg accacaagcc tgtggctgcccagttcctcc tgcagtttgc cttcagggac 1140 gacatgccac tggtgcggct ggaggtggcagatgagtggg tgcggcccga gcaggcggtg 1200 gtgaggtacc gcatggaaac agtgttcgcccgcagctcct gggactggat cggcttatac 1260 cgggtgggtt tccgccattg caaggactatgtggcttatg tctgggccaa acatgaagat 1320 gtggatggga atacctacca ggtaacattcagtgaggaat cactgcccaa gggccatgga 1380 gacttcatcc tgggctacta tagtcacaaccacagcatcc tcatcggcat cactgaaccc 1440 ttccagatct cgctgccttc ctcggagttggccagcagca gcacagacag ctcaggcacc 1500 agctcagagg gagaggatga cagcacactggagctccttg cacccaagtc ccgcagcccc 1560 agtcctggca agtccaagcg acaccgcagccgcagcccgg gactggccag gttccctggg 1620 cttgccctac ggccctcatc ccgtgaacgccgtggtgcca gccgtagccc ctcaccccag 1680 agccgccgcc tgtcccgagt ggctcctgacaggagcagta atggcagcag ccggggcagt 1740 agtgaagagg ggccctctgg gttgcctggcccctgggcct tcccaccagc tgtgcctcga 1800 agcctgggcc tgttgcccgc cttgcgcctagagactgtag accctggtgg tggtggctcc 1860 tggggacctg atcgggaggc cctggcgcccaacagcctgt ctcctagtcc ccagggccat 1920 cgggggctgg aggaaggggg cctggggccctgagggtggg gtaggcagat gggccaaggt 1980 gaccaccatt ctgcctcaat cttttgcaagcccacctgcc tctctcctgc tgctcctcca 2040 gctgtatctg cacctgcctc tctgtcctggccaggggtgg acaactgggg tcccccaaaa 2100 ctcagtcctg gcacctcaac tgtgacaatcagcaaagccc cacccaggcc cccatctggg 2160 atgatgggag agctctggca gatgtcccaatcctggaggt catccattag gaattaaatt 2220 ctccagcctc 2230 3 3042 DNA Homosapiens 3 acatggaggg ccagagcagc aggggcagca ggaggccagg gacccgggctggcctgggtt 60 ccctgcccat gccccagggt gttgcccaaa ctggggcacc ctccaaggtggactcaagtt 120 ttcagctccc agcaaagaag aacgcagccc taggaccctc ggaaccaaggttggctctgg 180 cacctgtagg gccacgggca gctatgtcag cttcctcgga aggaccgaggctggctctgg 240 catctccccg accaatcctg gctccactgt gtacccctga agggcagaaaacagctactg 300 cccaccgcag ctccagcctg gccccaacat ctgtgggcca gctggtgatgtctgcctcag 360 ctggaccaaa gcctccccca gcgaccacag gctcagttct ggctccgacgtccctggggc 420 tggtgatgcc tgcctcagca gggccaagat ctcccccagt caccctggggcccaatctgg 480 ccccaacctc cagagaccag aagcaggagc cacctgcctc cgtgggacccaagccaacac 540 tggcagcctc tggcctgagc ctggccctgg cttctgagga gcagcccccagaactcccct 600 ccaccccttc cccggtgccc agtccagttc tgtctccaac tcaggaacaggccctggctc 660 cagcatccac ggcatcaggc gcagcctctg tgggacagac atcagctagaaagagggatg 720 ccccagcccc tagacctctc cctgcttctg aggggcatct ccagcctccagctcagacat 780 ctggtcctac aggctcccca ccctgcatcc aaacctcccc agaccctcggctctccccct 840 ccttccgagc ccggcctgag gccctccaca gcagccctga ggatcctgttttgccacggc 900 caccccagac cttgcccttg gatgtgggcc agggtccttc agagcctggcactcactccc 960 ctggacttct gtcccccacc ttccggcctg gggccccctc aggccagactgtgcccccac 1020 ctctgcccaa gccaccccga tcacccagcc gttccccaag ccactccccgaatcgctctc 1080 cctgtgttcc cccagcccct gacatggccc tcccaaggct tggcacacagagtacagggc 1140 ctggcaggtg cctgagcccc aaccttcagg cccaagaagc cccagccccagtcaccacct 1200 cctcttctac atccaccctg tcatcctccc cttggtcagc tcagcctacctggaagagcg 1260 accccggctt ccggatcact gtggtcacat ggaacgtggg cactgccatgcccccagacg 1320 atgtcacatc cctcctccac ctgggcggtg gtgacgacag cgacggcgcagacatgatcg 1380 ccatagggtt gcaggaagtg aactccatgc tcaacaagcg actcaaggacgccctcttca 1440 cggaccagtg gagtgagctg ttcatggatg cgctagggcc cttcaacttcgtgctggtga 1500 gttcggtgag gatgcagggt gtcatcctgc tgctgttcgc caagtactaccacctgccct 1560 tcctgcgaga cgtgcagacc gactgcacgc gcactggcct gggcggctactggggtaaca 1620 agggtggcgt gagcgtgcgc ctggcggcct tcgggcacat gctctgcttcctgaactgcc 1680 acttgcctgc gcatatggac aaggcggagc agcgcaaaga caacttccagaccatcctca 1740 gcctccagca gttccaaggg ccgggcgcac agggcatcct ggatcatgacctcgtgttct 1800 ggttcgggga cctgaacttc cgcattgaga gctatgacct gcactttgtcaagtttgcca 1860 tcgacagtga ccagctccat cagctctggg agaaggacca gctcaacatggccaagaaca 1920 cctggcccat tctgaagggc tttcaggagg ggcccctcaa cttcgctcccaccttcaagt 1980 ttgatgtggg taccaacaaa tacgatacca gtgccaagaa acggaagccagcttggacag 2040 accgtatcct atggaaggtc aaggctccag gtgggggtcc cagcccctcaggacggaaga 2100 gccaccgact ccaggtgacg cagcacagct accgcagcca catggaatacacagtcagcg 2160 accacaagcc tgtggctgcc cagttcctcc tgcagtttgc cttcagggacgacatgccac 2220 tggtgcggct ggaggtggca gatgagtggg tgcggcccga gcaggcggtggtgaggtacc 2280 gcatggaaac agtgttcgcc cgcagctcct gggactggat cggcttataccgggtgggtt 2340 tccgccattg caaggactat gtggcttatg tctgggccaa acatgaagatgtggatggga 2400 atacctacca ggtaacattc agtgaggaat cactgcccaa gggccatggagacttcatcc 2460 tgggctacta tagtcacaac cacagcatcc tcatcggcat cactgaacccttccagatct 2520 cgctgccttc ctcggagttg gccagcagca gcacagacag ctcaggcaccagctcagagg 2580 gagaggatga cagcacactg gagctccttg cacccaagtc ccgcagccccagtcctggca 2640 agtccaagcg acaccgcagc cgcagcccgg gactggccag gttccctgggcttgccctac 2700 ggccctcatc ccgtgaacgc cgtggtgcca gccgtagccc ctcaccccagagccgccgcc 2760 tgtcccgagt ggctcctgac aggagcagta atggcagcag ccggggcagtagtgaagagg 2820 ggccctctgg gttgcctggc ccctgggcct tcccaccagc tgtgcctcgaagcctgggcc 2880 tgttgcccgc cttgcgccta gagactgtag accctggtgg tggtggctcctggggacctg 2940 atcgggaggc cctggcgccc aacagcctgt ctcctagtcc ccagggccatcgggggctgg 3000 aggaaggggg cctggggccc tgagggtggg gtaggcagat gg 3042 42757 DNA Homo sapiens misc_feature (939)..(939) “n” is A, C, G, or T 4cgtctctgac ggaagccggg gcggacggtc ggagtccgga agaaaaacag tccgcgacag 60ctaggcgcgt gagaccgacc gccgcgcagg gctgctctgg ccgggacccg ctggccggga 120gacgcgaacc tgccggacca ccgcgcgggg acgacggcgg ccatgagctc gcggaagctg 180agcgggccga aaggcaggag gctcagcata cacgtcgtga cttggaacgt ggcttcgnca 240gcgccccctc tagatctcag tgacctgctt cagctgaaca accggaacct caatcttgac 300atatatgtta ttggtttgca ggaattgaac tctgggatca taagcctcct ttccgatgct 360gcctttaatg actcgtggag cagtttcctc atggatgtgc tttcccctct gagcttcatc 420aaggtctccc atgtccgtat gcaggggatc ctcttactgg tctttgccaa gtatcagcat 480ttgccctata tccagattct gtctactaaa tccaccccca ctggcctgtt tgggtactgg 540gggaacaaag gtggagtcaa catctgcctg aagctttatg gctactatgt cagcatcatc 600aactgccacc tgcctcccca catttccaac aattaccagc ggctggagca ctttgaccgg 660atcctggaga tgcagaattg tgaggggcga gacatcccaa acatcctgga ccacgacctc 720attatctggt ttggagacat gaactttcgg atcgaggact ttgggttgca ctttgttcgg 780gaatccatta aaaatcggtg ctacggtggc ctgtgggaga aggaccagct cagcattgcc 840aagaaacatg acccgctgct ccgggagttc caggagggcc gcctactctt cccgcccacc 900tacaagtttg ataggaactc caacgactat gacaccagnt gagaaaaaac gcaagcctgc 960atggaccgat cgcatcctgt ggaggctgaa gcggcaggcc tgtgctggcc ccgacactcc 1020cataccgccg gcgtcacact tctccttgtc tctgaggggc tacagcagcc acatgacgta 1080cggcatcagc gaccacaagc ctgtctccgg cacgttcgac ttggagctga agccattggt 1140gtctgctccg ctgatcgtcc tgatgcccga ggacctgtgg accgtggaaa atgacatgat 1200ggtcagctac tcttcaacct cggacttccc cagcagcccg tgggactgga ttggactgta 1260caaggtgggg ctgcgggacg ttaatgacta cgtgtcctat gcctgggtcg gggacagcaa 1320ggtctcctgc agcgacaacc tgaaccaggt ttacatcgac atcagcaata tccctaccac 1380tgaagatgag tttctcctct gttactacag caacagtctg cgttctgtgg tggggataag 1440cagacccttc cagatcccgc ctggctcctt gagggaggac ccactgggtg aagcacagcc 1500acagatctga gccaggatgg gagtgaatcc caggcggagg ccagagctgg cagccagctc 1560tgcctttcca ctgccgggag tgnctggggn cccagcctgg ccccctgaag agacagccaa 1620gtgtcgtcca catactcctc ccagagtgag ctctaaccag gctcatttgc tctctccact 1680actcatctct ggaattagcc gcttaaatac aggtttttgt tgctgagatg tgagtgaaac 1740cagctagtgt gtcaacagtg aagacctggg gacagttctg cgtctcattt ctggattcct 1800accccctctt ctagtcttgc ccaagtagtc ctgccaggca catgccccat ttggcacagg 1860cctgcattct tgtcgtgccg tcctgggcct caggctgtct gggaggggag atgctcacat 1920ttgtacaggc tacatagact ggtgcaagca gtgctggatt ccaggagtct tggcatctca 1980tagcttgtcc ccgtgaggag tgagcagagg gtctgggatt tctgctttca gcaaaagcag 2040tctgactcag tgggcagaat ggaggggccc ctctagccag gctcttacgc catggttatg 2100agcaggttga tgagggtcct tcggccagca caaccttcct ccctactcac ggcatggagt 2160ctgactgcat ggaagttcca gatcctgaca gagagaactg ggaaggatcc aggttcgctt 2220ccgttggtag cttgagtccc atgcctccac cctgccatct gaggaagggg tgacaagtgg 2280tcaaggagct gtggccacag acttttccag ggtggtcctt ggcaggtgag gtgcgtctgt 2340gccacccttg tcaggagcca ttgacgacgg gccccccctg gaccccccgg gacctcagag 2400tgggggcagg cagaagggag aaccagctca agacattttg gaggatctgg ccctggggtt 2460cttcagagaa caccctctag gggctttggg gacatggcct gtccccacat ccagcacttg 2520cctccgccat ggtcactcgg cagccctttt cccaggagaa gacacctctg ggagcctgct 2580cagtgcttgt cctgccatcc tgtgtcctgg gactgagggt tactccagtt gctctgtgtt 2640gcatactctc ccccgcaagc ctgtgtatga agaattgtcc cctggcttcc agcaggccat 2700ggctggctgt tttgtgactg ttacattgtg caggggtaat tattagcgtg gctttta 2757 52786 DNA Homo sapiens 5 ggtgcgcggt agggccgtct ctgacggaag ccggggcgacggtcggagtc cggaagaaaa 60 acagtccgcg acagctaggc gcgtgatatc cggccgcccgcagtgctctg gccgggcgcc 120 cgctggccgg gagacgcgaa cctgccggac caccgcgcggggacgacggc ggccatgagc 180 tcgcggaagc tgagcgggcc gaaaggcagg aggctcagcatacacgtcgt gacttggaac 240 gtggcttcgg cagcgccccc tctagatctc agtgacctgcttcagctgaa caaccggaac 300 ctcaatcttg acatatatgt tattggtttg caggaattgaactctgggat cataagcctc 360 ctttccgatg ctgcctttaa tgactcgtgg agcagtttcctcatggatgt gctttcccct 420 ctgagcttca tcaaggtctc ccatgtccgt atgcaggggatcctcttact ggtctttgcc 480 aagtatcagc atttgcccta tatccagatt ctgtctactaaatccacccc cactggcctg 540 tttgggtact gggggaacaa aggtggagtc aacatctgcctgaagcttta tggctactat 600 gtcagcatca tcaactgcca cctgcctccc cacatttccaacaattacca gcggctggag 660 cactttgacc ggatcctgga gatgcagaat tgtgaggggcgagacatccc aaacatcctg 720 gaccacgacc tcattatctg gtttggagac atgaactttcggatcgagga ctttgggttg 780 cactttgttc gggaatccat taaaaatcgg tgctacggtggcctgtggga gaaggaccag 840 ctcagcattg ccaagaaaca tgacccgctg ctccgggagttccaggaggg ccgcctactc 900 ttcccgccca cctacaagtt tgataggaac tccaacgactatgacaccag tgagaaaaaa 960 cgcaagcctg catggaccga tcgcatcctg tggaggctgaagcggcagcc ctgtgctggc 1020 cccgacactc ccataccgcc ggcgtcacac ttctccttgtctctgagggg ctacagcagc 1080 cacatgacgt acggcatcag cgaccacaag cctgtctccggcacgttcga cttggagctg 1140 aagccattgg tgtctgctcc gctgatcgtc ctgatgcccgaggacctgtg gaccgtggaa 1200 aatgacatga tggtcagcta ctcttcaacc tcggacttccccagcagccc gtgggactgg 1260 attggactgt acaaggtggg gctgcgggac gttaatgactacgtgtccta tgcctgggtc 1320 ggggacagca aggtctcctg cagcgacaac ctgaaccaggtttacatcga catcagcaat 1380 atccctacca ctgaagatga gtttctcctc tgttactacagaaacagtct gcgttctgtg 1440 gtggggataa gaagaccctt ccagatcccg cctggctccttgagggagga cccactgggt 1500 gaagcacagc cacagatctg agccaggatg ggagtgaatcccaggcggag gccagagctg 1560 gcagccagct ctgcctttcc actgccggga gtgctgggggcccagcctgg ccccctgaag 1620 agacagccaa gtgtcgtcca catactcctc ccagagtgagctctaaccag gctcatttgc 1680 tctctccact actcatctct ggaattagcc gcttaaatacaggtttttgt tgctgagatg 1740 tgagtgaaac cagctagtgt gtcaacagtg aagacctggggacagttctg cgtctcattt 1800 ctggattcct accccctctt ctagtcttgc ccaagtagtcctgccaggca catgccccat 1860 ttggcacagg cctgcattct tgtcgtgccg tcctgggcctcaggctgtct gggaggggag 1920 atgctcacat ttgtacaggc tacatagact ggtgcaagcagtgctggatt ccaggagtct 1980 tggcatctca tagcttgtcc ccgtgaggag tgagcagagggtctgggatt tctgctttca 2040 gcaaaagcag tctgactcag tgggcagaat ggaggggcccctctagccag gctcttacgc 2100 catggttatg agcaggttga tgagggtcct tcggccagcacaaccttcct ccctactcac 2160 ggcatggagt ctgactgcat ggaagttcca gatcctgacagagagaactg ggaaggatcc 2220 aggttcgctt ccgttggtag cttgagtccc atgcctccaccctgccatct gaggaagggg 2280 tgacaagtgg tcaaggagct gtggccacag acttttccagggtggtcctt ggcaggtgag 2340 gtgcgtctgt cccacccttg tcaggagcca ttgacgacgggccccccctg gaccccccgg 2400 gacctcagag tgggggcagg cagaagggag aaccagctcaagacattttg gaggatctgg 2460 ccctggggtt cttcagagaa caccctctag gggctttggggacatggcct gtccccacat 2520 ccagcacttg cctccgccat ggtcactcgg cagcccttttcccaggagaa gacacctctg 2580 ggagcctgct cagtgcttgt cctgccatcc tgtgtcctgggactgagggt tactccagtt 2640 gctctgtgtt gcatactctc ccccgcaagc ctgtgtatgaagaattgtcc cctggcttcc 2700 agcaggccat ggctggctgt tttgtgactg ttacattgtgcaggggtaat tattagcgtg 2760 gcttttaaaa aaaaaaaaaa aaaaaa 2786 6 3015 DNAHomo sapiens 6 ggtgcgcggt agggccgtct ctgacggaag ccggggcgac ggtcggagtccggaagaaaa 60 acagtccgcg acagctaggc gcgtgatatc cggccgcccg cagtgctctggccgggcgcc 120 cgctggccgg gagacgcgaa cctgccggac caccgcgcgg ggacgacggcggccatgagc 180 tcgcggaagc tgagcgggcc gaaaggcagg aggctcagca tacatcaggaggtctgcctg 240 atcccatggt gaaccccggg aatccgaaat cagattgaga taagatcctttagggaagtg 300 acttagcctg gtctcttgcc tgctctttca cggggaacaa cgctaatcgcccacttagtc 360 taagttacga tgcttggatt tgctgctaat cgtcggattt gagagttggaacaagaaatc 420 cggacttttg ctctccatcc tcttagacat acacgtcgtg acttggaacgtggcttcggc 480 agcgccccct ctagatctca gtgacctgct tcagctgaac aaccggaacctcaatcttga 540 catatatgtt attggtttgc aggaattgaa ctctgggatc ataagcctcctttccgatgc 600 tgcctttaat gactcgtgga gcagtttcct catggatgtg ctttcccctctgagcttcat 660 caaggtctcc catgtccgta tgcaggggat cctcttactg gtctttgccaagtatcagca 720 tttgccctat atccagattc tgtctactaa atccaccccc actggcctgtttgggtactg 780 ggggaacaaa ggtggagtca acatctgcct gaagctttat ggctactatgtcagcatcat 840 caactgccac ctgcctcccc acatttccaa caattaccag cggctggagcactttgaccg 900 gatcctggag atgcagaatt gtgaggggcg agacatccca aacatcctggaccacgacct 960 cattatctgg tttggagaca tgaactttcg gatcgaggac tttgggttgcactttgttcg 1020 ggaatccatt aaaaatcggt gctacggtgg cctgtgggag aaggaccagctcagcattgc 1080 caagaaacat gacccgctgc tccgggagtt ccaggagggc cgcctactcttcccgcccac 1140 ctacaagttt gataggaact ccaacgacta tgacaccagt gagaaaaaacgcaagcctgc 1200 atggaccgat cgcatcctgt ggaggctgaa gcggcagccc tgtgctggccccgacactcc 1260 cataccgccg gcgtcacact tctccttgtc tctgaggggc tacagcagccacatgacgta 1320 cggcatcagc gaccacaagc ctgtctccgg cacgttcgac ttggagctgaagccattggt 1380 gtctgctccg ctgatcgtcc tgatgcccga ggacctgtgg accgtggaaaatgacatgat 1440 ggtcagctac tcttcaacct cggacttccc cagcagcccg tgggactggattggactgta 1500 caaggtgggg ctgcgggacg ttaatgacta cgtgtcctat gcctgggtcggggacagcaa 1560 ggtctcctgc agcgacaacc tgaaccaggt ttacatcgac atcagcaatatccctaccac 1620 tgaagatgag tttctcctct gttactacag aaacagtctg cgttctgtggtggggataag 1680 aagacccttc cagatcccgc ctggctcctt gagggaggac ccactgggtgaagcacagcc 1740 acagatctga gccaggatgg gagtgaatcc caggcggagg ccagagctggcagccagctc 1800 tgcctttcca ctgccgggag tgctgggggc ccagcctggc cccctgaagagacagccaag 1860 tgtcgtccac atactcctcc cagagtgagc tctaaccagg ctcatttgctctctccacta 1920 ctcatctctg gaattagccg cttaaataca ggtttttgtt gctgagatgtgagtgaaacc 1980 agctagtgtg tcaacagtga agacctgggg acagttctgc gtctcatttctggattccta 2040 ccccctcttc tagtcttgcc caagtagtcc tgccaggcac atgccccatttggcacaggc 2100 ctgcattctt gtcgtgccgt cctgggcctc aggctgtctg ggaggggagatgctcacatt 2160 tgtacaggct acatagactg gtgcaagcag tgctggattc caggagtcttggcatctcat 2220 agcttgtccc cgtgaggagt gagcagaggg tctgggattt ctgctttcagcaaaagcagt 2280 ctgactcagt gggcagaatg gaggggcccc tctagccagg ctcttacgccatggttatga 2340 gcaggttgat gagggtcctt cggccagcac aaccttcctc cctactcacggcatggagtc 2400 tgactgcatg gaagttccag atcctgacag agagaactgg gaaggatccaggttcgcttc 2460 cgttggtagc ttgagtccca tgcctccacc ctgccatctg aggaaggggtgacaagtggt 2520 caaggagctg tggccacaga cttttccagg gtggtccttg gcaggtgaggtgcgtctgtc 2580 ccacccttgt caggagccat tgacgacggg ccccccctgg accccccgggacctcagagt 2640 gggggcaggc agaagggaga accagctcaa gacattttgg aggatctggccctggggttc 2700 ttcagagaac accctctagg ggctttgggg acatggcctg tccccacatccagcacttgc 2760 ctccgccatg gtcactcggc agcccttttc ccaggagaag acacctctgggagcctgctc 2820 agtgcttgtc ctgccatcct gtgtcctggg actgagggtt actccagttgctctgtgttg 2880 catactctcc cccgcaagcc tgtgtatgaa gaattgtccc ctggcttccagcaggccatg 2940 gctggctgtt ttgtgactgt tacattgtgc aggggtaatt attagcgtggcttttaaaaa 3000 aaaaaaaaaa aaaaa 3015 7 2684 DNA Homo sapiensmisc_feature (167)..(167) “n” is A, C, G, or T 7 gagaccggcc gcccgcagggctgctctggc cgggacccgc tggccgggag acgcgaacct 60 gccggaccac cgcgcggggacgacggcggc catgagctcg cggaagctga gcgggccgaa 120 aggcaggagg ctcagcatacacgtcgtgac ttggaacgtg gcttcgncag cgccccctct 180 agatctcagt gacctgcttcagctgaacaa ccggaacctc aatcttgaca tatatgttat 240 tggtttgcag gaattgaactctgggatcat aagcctcctt tccgatgctg cctttaatga 300 ctcgtggagc agtttcctcatggatgtgct ttcccctctg agcttcatca aggtctccca 360 tgtccgtatg caggggatcctcttactggt ctttgccaag tatcagcatt tgccctatat 420 ccagattctg tctactaaatccacccccac tggcctgttt gggtactggg ggaacaaagg 480 tggagtcaac atctgcctgaagctttatgg ctactatgtc agcatcatca actgccacct 540 gcctccccac atttccaacaattaccagcg gctggagcac tttgaccgga tcctggagat 600 gcagaattgt gaggggcgagacatcccaaa catcctggac cacgacctca ttatctggtt 660 tggagacatg aactttcggatcgaggactt tgggttgcac tttgttcggg aatccattaa 720 aaatcggtgc tacggtggcctgtgggagaa ggaccagctc agcattgcca agaaacatga 780 cccgctgctc cgggagttccaggagggccg cctactcttc ccgcccacct acaagtttga 840 taggaactcc aacgactatgacaccagtga gaaaaaacgc aagcctgcat ggaccgatcg 900 catcctgtgg aggctgaagcggcaggcctg tgctggcccc gacactccca taccgccggc 960 gtcacacttc tccttgtctctgaggggcta cagcagccac atgacgtacg gcatcagcga 1020 ccacaagcct gtctccggcacgttcgactt ggagctgaag ccattggtgt ctgctccgct 1080 gatcgtcctg atgcccgaggacctgtggac cgtggaaaat gacatgatgg tcagctactc 1140 ttcaacctcg gacttccccagcagcccgtg ggactggatt ggactgtaca aggtggggct 1200 gcgggacgtt aatgactacgtgtcctatgc ctgggtcggg gacagcaagg tctcctgcag 1260 cgacaacctg aaccaggtttacatcgacat cagcaatatc cctaccactg aagatgagtt 1320 tctcctctgt tactacagcaacagtctgcg ttctgtggtg gggataagca gacccttcca 1380 gatcccgcct ggctccttgagggaggaccc actgggtgaa gcacagccac agatctgagc 1440 caggatggga gtgaatcccaggcggaggcc agagctggca gccagctctg cctttccact 1500 gccgggagtg nctggggncccagcctggcc ccctgaagag acagccaagt gtcgtccaca 1560 tactcctccc agagtgagctctaaccaggc tcatttgctc tctccactac tcatctctgg 1620 aattagccgc ttaaatacaggtttttgttg ctgagatgtg agtgaaacca gctagtgtgt 1680 caacagtgaa gacctggggacagttctgcg tctcatttct ggattcctac cccctcttct 1740 agtcttgccc aagtagtcctgccaggcaca tgccccattt ggcacaggcc tgcattcttg 1800 tcgtgccgtc ctgggcctcaggctgtctgg gaggggagat gctcacattt gtacaggcta 1860 catagactgg tgcaagcagtgctggattcc aggagtcttg gcatctcata gcttgtcccc 1920 gtgaggagtg agcagagggtctgggatttc tgctttcagc aaaagcagtc tgactcagtg 1980 ggcagaatgg aggggcccctctagccaggc tcttacgcca tggttatgag caggttgatg 2040 agggtccttc ggccagcacaaccttcctcc ctactcacgg catggagtct gactgcatgg 2100 aagttccaga tcctgacagagagaactggg aaggatccag gttcgcttcc gttggtagct 2160 tgagtcccat gcctccaccctgccatctga ggaaggggtg acaagtggtc aaggagctgt 2220 ggccacagac ttttccagggtggtccttgg caggtgaggt gcgtctgtgc cacccttgtc 2280 aggagccatt gacgacgggccccccctgga ccccccggga cctcagagtg ggggcaggca 2340 gaagggagaa ccagctcaagacattttgga ggatctggcc ctggggttct tcagagaaca 2400 ccctctaggg gctttggggacatggcctgt ccccacatcc agcacttgcc tccgccatgg 2460 tcactcggca gcccttttcccaggagaaga cacctctggg agcctgctca gtgcttgtcc 2520 tgccatcctg tgtcctgggactgagggtta ctccagttgc tctgtgttgc atactctccc 2580 ccgcaagcct gtgtatgaagaattgtcccc tggcttccag caggccatgg ctggctgttt 2640 tgtgactgtt acattgtgcaggggtaatta ttagcgtggc tttt 2684 8 1355 DNA Homo sapiens 8 ggccatgagctcgcggaagc tgagcgggcc gaaaggcagg aggctcagca tacacgtcgt 60 gacttggaacgtggcttcgg cagcgccccc tctagatctc agtgacctgc ttcagctgaa 120 caaccggaacctcaatcttg acatatatgt tattggtttg caggaattga actctgggat 180 cataagcctcctttccgatg ctgcctttaa tgactcgtgg agcagtttcc tcatggatgt 240 gctttcccctctgagcttca tcaaggtctc ccatgtccgt atgcagggga tcctcttact 300 ggtctttgccaagtatcagc atttgcccta tatccagatt ctgtctacta aatccacccc 360 cactggcctgtttgggtact gggggaacaa aggtggagtc aacatctgcc tgaagcttta 420 tggctactatgtcagcatca tcaactgcca cctgcctccc cacatttcca acaattacca 480 gcggctggagcactttgacc ggatcctgga gatgcagaat tgtgaggggc gagacatccc 540 aaacatcctggaccacgacc tcattatctg gtttggagac atgaactttc ggatcgagga 600 ctttgggttgcactttgttc gggaatccat taaaaatcgg tgctacggtg gcctgtggga 660 gaaggaccagctcagcattg ccaagaaaca tgacccgctg ctccgggagt tccaggaggg 720 ccgcctactcttcccgccca cctacaagtt tgataggaac tccaacgact atgacaccag 780 tgagaaaaaacgcaagcctg catggaccga tcgcatcctg tggaggctga agcggcagcc 840 ctgtgctggccccgacactc ccataccgcc ggcgtcacac ttctccttgt ctctgagggg 900 ctacagcagccacatgacgt acggcatcag cgaccacaag cctgtctccg gcacgttcga 960 cttggagctgaagccattgg tgtctgctcc gctgatcgtc ctgatgcccg aggacctgtg 1020 gaccgtggaaaatgacatga tggtcagcta ctcttcaacc tcggacttcc ccagcagccc 1080 gtgggactggattggactgt acaaggtggg gctgcgggac gttaatgact acgtgtccta 1140 tgcctgggtcggggacagca aggtctcctg cagcgacaac ctgaaccagg tttacatcga 1200 catcagcaatatccctacca ctgaagatga gtttctcctc tgttactaca gcaacagtct 1260 gcgttctgtggtggggataa gcagaccctt ccagatcccg cctggctcct tgagggagga 1320 cccactgggtgaagcacagc cacagatctg agcca 1355 9 1126 DNA Homo sapiens 9 tcatggatgtgctttcccct ctgagcttca tcaaggtctc ccatgtccgt atgcagggga 60 tcctcttactggtctttgcc aagtatcagc atttgcccta tatccagatt ctgtctacta 120 aatccacccccactggcctg tttgggtact gggggaacaa aggtggagtc aacatctgcc 180 tgaagctttatggctactat gtcagcatca tcaactgcca cctgcctccc cacatttcca 240 acaattaccagcggctggag cactttgacc ggatcctgga gatgcagaat tgtgaggggc 300 gagacatcccaaacatcctg gaccacgacc tcattatctg gtttggagac atgaactttc 360 ggatcgaggactttgggttg cactttgttc gggaatccat taaaaatcgg tgctacggtg 420 gcctgtgggagaaggaccag ctcagcattg ccaagaaaca tgacccgctg ctccgggagt 480 tccaggagggccgcctactc ttcccgccca cctacaagtt tgataggaac tccaacgact 540 atgacaccagtgagaaaaaa cgcaagcctg catggaccga tcgcatcctg tggaggctga 600 agcggcagccctgtgctggc cccgacactc ccataccgcc ggcgtcacac ttctccttgt 660 ctctgaggggctacagcagc cacatgacgt acggcatcag cgaccacaag cctgtctccg 720 gcacgttcgacttggagctg aagccattgg tgtctgctcc gctgatcgtc ctgatgcccg 780 aggacctgtggaccgtggaa aatgacatga tggtcagcta ctcttcaacc tcggacttcc 840 ccagcagcccgtgggactgg attggactgt acaaggtggg gctgcgggac gttaatgact 900 acgtgtcctatgcctgggtc ggggacagca aggtctcctg cagcgacaac ctgaaccagg 960 tttacatcgacatcagcaat atccctacca ctgaagatga gtttctcctc tgttactaca 1020 gcaacagtctgcgttctgtg gtggggataa gcagaccctt ccagatcccg cctggctcct 1080 tgagggaggacccactgggt gaagcacagc cacagatctg agccag 1126 10 1056 PRT Homo sapiens 10Glu Pro Arg Glu Ser Arg Leu Pro Gly Ala Ala Asp Met Glu Gly Gln 1 5 1015 Ser Ser Arg Gly Ser Arg Arg Pro Gly Thr Arg Ala Gly Leu Gly Ser 20 2530 Leu Pro Met Pro Gln Gly Val Ala Gln Thr Gly Ala Pro Ser Lys Val 35 4045 Asp Ser Ser Phe Gln Leu Pro Ala Lys Lys Asn Ala Ala Leu Gly Pro 50 5560 Ser Glu Pro Arg Leu Ala Leu Ala Pro Val Gly Pro Arg Ala Ala Met 65 7075 80 Ser Ala Ser Ser Glu Gly Pro Arg Leu Ala Leu Ala Ser Pro Arg Pro 8590 95 Ile Leu Ala Pro Leu Cys Thr Pro Glu Gly Gln Lys Thr Ala Thr Ala100 105 110 His Arg Ser Ser Ser Leu Ala Pro Thr Ser Val Gly Gln Leu ValMet 115 120 125 Ser Ala Ser Ala Gly Pro Lys Pro Pro Pro Ala Thr Thr GlySer Val 130 135 140 Leu Ala Pro Thr Ser Leu Gly Leu Val Met Pro Ala SerAla Gly Pro 145 150 155 160 Arg Ser Pro Pro Val Thr Leu Gly Pro Asn LeuAla Pro Thr Ser Arg 165 170 175 Asp Gln Lys Gln Glu Pro Pro Ala Ser ValGly Pro Lys Pro Thr Leu 180 185 190 Ala Ala Ser Gly Leu Ser Leu Ala LeuAla Ser Glu Glu Gln Pro Pro 195 200 205 Glu Leu Pro Ser Thr Pro Ser ProVal Pro Ser Pro Val Leu Ser Pro 210 215 220 Thr Gln Glu Gln Ala Leu AlaPro Ala Ser Thr Ala Ser Gly Ala Ala 225 230 235 240 Ser Val Gly Gln ThrSer Ala Arg Lys Arg Asp Ala Pro Ala Pro Arg 245 250 255 Pro Leu Pro AlaSer Glu Gly His Leu Gln Pro Pro Ala Gln Thr Ser 260 265 270 Gly Pro ThrGly Ser Pro Pro Cys Ile Gln Thr Ser Pro Asp Pro Arg 275 280 285 Leu SerPro Ser Phe Arg Ala Arg Pro Glu Ala Leu His Ser Ser Pro 290 295 300 GluAsp Pro Val Leu Pro Arg Pro Pro Gln Thr Leu Pro Leu Asp Val 305 310 315320 Gly Gln Gly Pro Ser Glu Pro Gly Thr His Ser Pro Gly Leu Leu Ser 325330 335 Pro Thr Phe Arg Pro Gly Ala Pro Ser Gly Gln Thr Val Pro Pro Pro340 345 350 Leu Pro Lys Pro Pro Arg Ser Pro Ser Arg Ser Pro Ser His SerPro 355 360 365 Asn Arg Ser Pro Cys Val Pro Pro Ala Pro Asp Met Ala LeuPro Arg 370 375 380 Leu Gly Thr Gln Ser Thr Gly Pro Gly Arg Cys Leu SerPro Asn Leu 385 390 395 400 Gln Ala Gln Glu Ala Pro Ala Pro Val Thr ThrSer Ser Ser Thr Ser 405 410 415 Thr Leu Ser Ser Ser Pro Trp Ser Ala GlnPro Thr Trp Lys Ser Asp 420 425 430 Pro Gly Phe Arg Ile Thr Val Val ThrTrp Asn Val Gly Thr Ala Met 435 440 445 Pro Pro Asp Asp Val Thr Ser LeuLeu His Leu Gly Gly Gly Asp Asp 450 455 460 Ser Asp Gly Ala Asp Met IleAla Ile Gly Leu Gln Glu Val Asn Ser 465 470 475 480 Met Leu Asn Lys ArgLeu Lys Asp Ala Leu Phe Thr Asp Gln Trp Ser 485 490 495 Glu Leu Phe MetAsp Ala Leu Gly Pro Phe Asn Phe Val Leu Val Thr 500 505 510 His Pro SerPro Pro Gly Gln Pro Glu Thr Leu Leu Asn Ser Trp Leu 515 520 525 Gln LeuTyr Pro Gly Ser Leu Trp Gly Pro Leu Gly Leu Cys Gly Trp 530 535 540 ValSer Ser Val Arg Met Gln Gly Val Ile Leu Leu Leu Phe Ala Lys 545 550 555560 Tyr Tyr His Leu Pro Phe Leu Arg Asp Val Gln Thr Asp Cys Thr Arg 565570 575 Thr Gly Leu Gly Gly Tyr Trp Gly Asn Lys Gly Gly Val Ser Val Arg580 585 590 Leu Ala Ala Phe Gly His Met Leu Cys Phe Leu Asn Cys His LeuPro 595 600 605 Ala His Met Asp Lys Ala Glu Gln Arg Lys Asp Asn Phe GlnThr Ile 610 615 620 Leu Ser Leu Gln Gln Phe Gln Gly Pro Gly Ala Gln GlyIle Leu Asp 625 630 635 640 His Glu Tyr Gly Leu Gly Leu Val Phe Trp PheGly Asp Leu Asn Phe 645 650 655 Arg Ile Glu Ser Tyr Asp Leu His Phe ValLys Phe Ala Ile Asp Ser 660 665 670 Asp Gln Leu His Gln Leu Trp Glu LysAsp Gln Leu Asn Met Ala Lys 675 680 685 Asn Thr Trp Pro Ile Leu Lys GlyPhe Gln Glu Gly Pro Leu Asn Phe 690 695 700 Ala Pro Thr Phe Lys Phe AspVal Gly Thr Asn Lys Tyr Asp Thr Ser 705 710 715 720 Ala Lys Lys Arg LysPro Ala Trp Thr Asp Arg Ile Leu Trp Lys Val 725 730 735 Lys Ala Pro GlyGly Gly Pro Ser Pro Ser Gly Arg Lys Ser His Arg 740 745 750 Leu Gln ValThr Gln His Ser Tyr Arg Ser His Met Glu Tyr Thr Val 755 760 765 Ser AspHis Lys Pro Val Ala Ala Gln Phe Leu Leu Gln Phe Ala Phe 770 775 780 ArgAsp Asp Met Pro Leu Val Arg Leu Glu Val Ala Asp Glu Trp Val 785 790 795800 Arg Pro Glu Gln Ala Val Val Arg Tyr Arg Met Glu Thr Val Phe Ala 805810 815 Arg Ser Ser Trp Asp Trp Ile Gly Leu Tyr Arg Val Gly Phe Arg His820 825 830 Cys Lys Asp Tyr Val Ala Tyr Val Trp Ala Lys His Glu Asp ValAsp 835 840 845 Gly Asn Thr Tyr Gln Val Thr Phe Ser Glu Glu Ser Leu ProLys Gly 850 855 860 His Gly Asp Phe Ile Leu Gly Tyr Tyr Ser His Asn HisSer Ile Leu 865 870 875 880 Ile Gly Ile Thr Glu Pro Phe Gln Ile Ser LeuPro Ser Ser Glu Leu 885 890 895 Ala Ser Ser Ser Thr Asp Ser Ser Gly ThrSer Ser Glu Gly Glu Asp 900 905 910 Asp Ser Thr Leu Glu Leu Leu Ala ProLys Ser Arg Ser Pro Ser Pro 915 920 925 Gly Lys Ser Lys Arg His Arg SerArg Ser Pro Gly Leu Ala Arg Phe 930 935 940 Pro Gly Leu Ala Leu Arg ProSer Ser Arg Glu Arg Arg Gly Ala Ser 945 950 955 960 Arg Ser Pro Ser ProGln Ser Arg Arg Leu Ser Arg Val Ala Pro Asp 965 970 975 Arg Ser Ser AsnGly Ser Ser Arg Gly Ser Ser Glu Glu Gly Pro Ser 980 985 990 Gly Leu ProGly Pro Trp Ala Phe Pro Pro Ala Val Pro Arg Ser Leu 995 1000 1005 GlyLeu Leu Pro Ala Leu Arg Leu Glu Thr Val Asp Pro Gly Gly 1010 1015 1020Gly Gly Ser Trp Gly Pro Asp Arg Glu Ala Leu Ala Pro Asn Ser 1025 10301035 Leu Ser Pro Ser Pro Gln Gly His Arg Gly Leu Glu Glu Gly Gly 10401045 1050 Leu Gly Pro 1055 11 478 PRT Homo sapiens misc_feature(56)..(56) “X” is any amino acid 11 Arg Pro Ala Ala Arg Arg Ala Ala LeuAla Gly Thr Arg Trp Pro Gly 1 5 10 15 Asp Ala Asn Leu Pro Asp His ArgAla Gly Thr Thr Ala Ala Met Ser 20 25 30 Ser Arg Lys Leu Ser Gly Pro LysGly Arg Arg Leu Ser Ile His Val 35 40 45 Val Thr Trp Asn Val Ala Ser XaaAla Pro Pro Leu Asp Leu Ser Asp 50 55 60 Leu Leu Gln Leu Asn Asn Arg AsnLeu Asn Leu Asp Ile Tyr Val Ile 65 70 75 80 Gly Leu Gln Glu Leu Asn SerGly Ile Ile Ser Leu Leu Ser Asp Ala 85 90 95 Ala Phe Asn Asp Ser Trp SerSer Phe Leu Met Asp Val Leu Ser Pro 100 105 110 Leu Ser Phe Ile Lys ValSer His Val Arg Met Gln Gly Ile Leu Leu 115 120 125 Leu Val Phe Ala LysTyr Gln His Leu Pro Tyr Ile Gln Ile Leu Ser 130 135 140 Thr Lys Ser ThrPro Thr Gly Leu Phe Gly Tyr Trp Gly Asn Lys Gly 145 150 155 160 Gly ValAsn Ile Cys Leu Lys Leu Tyr Gly Tyr Tyr Val Ser Ile Ile 165 170 175 AsnCys His Leu Pro Pro His Ile Ser Asn Asn Tyr Gln Arg Leu Glu 180 185 190His Phe Asp Arg Ile Leu Glu Met Gln Asn Cys Glu Gly Arg Asp Ile 195 200205 Pro Asn Ile Leu Asp His Asp Leu Ile Ile Trp Phe Gly Asp Met Asn 210215 220 Phe Arg Ile Glu Asp Phe Gly Leu His Phe Val Arg Glu Ser Ile Lys225 230 235 240 Asn Arg Cys Tyr Gly Gly Leu Trp Glu Lys Asp Gln Leu SerIle Ala 245 250 255 Lys Lys His Asp Pro Leu Leu Arg Glu Phe Gln Glu GlyArg Leu Leu 260 265 270 Phe Pro Pro Thr Tyr Lys Phe Asp Arg Asn Ser AsnAsp Tyr Asp Thr 275 280 285 Ser Glu Lys Lys Arg Lys Pro Ala Trp Thr AspArg Ile Leu Trp Arg 290 295 300 Leu Lys Arg Gln Ala Cys Ala Gly Pro AspThr Pro Ile Pro Pro Ala 305 310 315 320 Ser His Phe Ser Leu Ser Leu ArgGly Tyr Ser Ser His Met Thr Tyr 325 330 335 Gly Ile Ser Asp His Lys ProVal Ser Gly Thr Phe Asp Leu Glu Leu 340 345 350 Lys Pro Leu Val Ser AlaPro Leu Ile Val Leu Met Pro Glu Asp Leu 355 360 365 Trp Thr Val Glu AsnAsp Met Met Val Ser Tyr Ser Ser Thr Ser Asp 370 375 380 Phe Pro Ser SerPro Trp Asp Trp Ile Gly Leu Tyr Lys Val Gly Leu 385 390 395 400 Arg AspVal Asn Asp Tyr Val Ser Tyr Ala Trp Val Gly Asp Ser Lys 405 410 415 ValSer Cys Ser Asp Asn Leu Asn Gln Val Tyr Ile Asp Ile Ser Asn 420 425 430Ile Pro Thr Thr Glu Asp Glu Phe Leu Leu Cys Tyr Tyr Ser Asn Ser 435 440445 Leu Arg Ser Val Val Gly Ile Ser Arg Pro Phe Gln Ile Pro Pro Gly 450455 460 Ser Leu Arg Glu Asp Pro Leu Gly Glu Ala Gln Pro Gln Ile 465 470475 12 448 PRT Homo sapiens 12 Met Ser Ser Arg Lys Leu Ser Gly Pro LysGly Arg Arg Leu Ser Ile 1 5 10 15 His Val Val Thr Trp Asn Val Ala SerAla Ala Pro Pro Leu Asp Leu 20 25 30 Ser Asp Leu Leu Gln Leu Asn Asn ArgAsn Leu Asn Leu Asp Ile Tyr 35 40 45 Val Ile Gly Leu Gln Glu Leu Asn SerGly Ile Ile Ser Leu Leu Ser 50 55 60 Asp Ala Ala Phe Asn Asp Ser Trp SerSer Phe Leu Met Asp Val Leu 65 70 75 80 Ser Pro Leu Ser Phe Ile Lys ValSer His Val Arg Met Gln Gly Ile 85 90 95 Leu Leu Leu Val Phe Ala Lys TyrGln His Leu Pro Tyr Ile Gln Ile 100 105 110 Leu Ser Thr Lys Ser Thr ProThr Gly Leu Phe Gly Tyr Trp Gly Asn 115 120 125 Lys Gly Gly Val Asn IleCys Leu Lys Leu Tyr Gly Tyr Tyr Val Ser 130 135 140 Ile Ile Asn Cys HisLeu Pro Pro His Ile Ser Asn Asn Tyr Gln Arg 145 150 155 160 Leu Glu HisPhe Asp Arg Ile Leu Glu Met Gln Asn Cys Glu Gly Arg 165 170 175 Asp IlePro Asn Ile Leu Asp His Asp Leu Ile Ile Trp Phe Gly Asp 180 185 190 MetAsn Phe Arg Ile Glu Asp Phe Gly Leu His Phe Val Arg Glu Ser 195 200 205Ile Lys Asn Arg Cys Tyr Gly Gly Leu Trp Glu Lys Asp Gln Leu Ser 210 215220 Ile Ala Lys Lys His Asp Pro Leu Leu Arg Glu Phe Gln Glu Gly Arg 225230 235 240 Leu Leu Phe Pro Pro Thr Tyr Lys Phe Asp Arg Asn Ser Asn AspTyr 245 250 255 Asp Thr Ser Glu Lys Lys Arg Lys Pro Ala Trp Thr Asp ArgIle Leu 260 265 270 Trp Arg Leu Lys Arg Gln Pro Cys Ala Gly Pro Asp ThrPro Ile Pro 275 280 285 Pro Ala Ser His Phe Ser Leu Ser Leu Arg Gly TyrSer Ser His Met 290 295 300 Thr Tyr Gly Ile Ser Asp His Lys Pro Val SerGly Thr Phe Asp Leu 305 310 315 320 Glu Leu Lys Pro Leu Val Ser Ala ProLeu Ile Val Leu Met Pro Glu 325 330 335 Asp Leu Trp Thr Val Glu Asn AspMet Met Val Ser Tyr Ser Ser Thr 340 345 350 Ser Asp Phe Pro Ser Ser ProTrp Asp Trp Ile Gly Leu Tyr Lys Val 355 360 365 Gly Leu Arg Asp Val AsnAsp Tyr Val Ser Tyr Ala Trp Val Gly Asp 370 375 380 Ser Lys Val Ser CysSer Asp Asn Leu Asn Gln Val Tyr Ile Asp Ile 385 390 395 400 Ser Asn IlePro Thr Thr Glu Asp Glu Phe Leu Leu Cys Tyr Tyr Arg 405 410 415 Asn SerLeu Arg Ser Val Val Gly Ile Arg Arg Pro Phe Gln Ile Pro 420 425 430 ProGly Ser Leu Arg Glu Asp Pro Leu Gly Glu Ala Gln Pro Gln Ile 435 440 44513 372 PRT Homo sapiens 13 Met Asp Val Leu Ser Pro Leu Ser Phe Ile LysVal Ser His Val Arg 1 5 10 15 Met Gln Gly Ile Leu Leu Leu Val Phe AlaLys Tyr Gln His Leu Pro 20 25 30 Tyr Ile Gln Ile Leu Ser Thr Lys Ser ThrPro Thr Gly Leu Phe Gly 35 40 45 Tyr Trp Gly Asn Lys Gly Gly Val Asn IleCys Leu Lys Leu Tyr Gly 50 55 60 Tyr Tyr Val Ser Ile Ile Asn Cys His LeuPro Pro His Ile Ser Asn 65 70 75 80 Asn Tyr Gln Arg Leu Glu His Phe AspArg Ile Leu Glu Met Gln Asn 85 90 95 Cys Glu Gly Arg Asp Ile Pro Asn IleLeu Asp His Asp Leu Ile Ile 100 105 110 Trp Phe Gly Asp Met Asn Phe ArgIle Glu Asp Phe Gly Leu His Phe 115 120 125 Val Arg Glu Ser Ile Lys AsnArg Cys Tyr Gly Gly Leu Trp Glu Lys 130 135 140 Asp Gln Leu Ser Ile AlaLys Lys His Asp Pro Leu Leu Arg Glu Phe 145 150 155 160 Gln Glu Gly ArgLeu Leu Phe Pro Pro Thr Tyr Lys Phe Asp Arg Asn 165 170 175 Ser Asn AspTyr Asp Thr Ser Glu Lys Lys Arg Lys Pro Ala Trp Thr 180 185 190 Asp ArgIle Leu Trp Arg Leu Lys Arg Gln Pro Cys Ala Gly Pro Asp 195 200 205 ThrPro Ile Pro Pro Ala Ser His Phe Ser Leu Ser Leu Arg Gly Tyr 210 215 220Ser Ser His Met Thr Tyr Gly Ile Ser Asp His Lys Pro Val Ser Gly 225 230235 240 Thr Phe Asp Leu Glu Leu Lys Pro Leu Val Ser Ala Pro Leu Ile Val245 250 255 Leu Met Pro Glu Asp Leu Trp Thr Val Glu Asn Asp Met Met ValSer 260 265 270 Tyr Ser Ser Thr Ser Asp Phe Pro Ser Ser Pro Trp Asp TrpIle Gly 275 280 285 Leu Tyr Lys Val Gly Leu Arg Asp Val Asn Asp Tyr ValSer Tyr Ala 290 295 300 Trp Val Gly Asp Ser Lys Val Ser Cys Ser Asp AsnLeu Asn Gln Val 305 310 315 320 Tyr Ile Asp Ile Ser Asn Ile Pro Thr ThrGlu Asp Glu Phe Leu Leu 325 330 335 Cys Tyr Tyr Arg Asn Ser Leu Arg SerVal Val Gly Ile Arg Arg Pro 340 345 350 Phe Gln Ile Pro Pro Gly Ser LeuArg Glu Asp Pro Leu Gly Glu Ala 355 360 365 Gln Pro Gln Ile 370 14 448PRT Homo sapiens 14 Met Ser Ser Arg Lys Leu Ser Gly Pro Lys Gly Arg ArgLeu Ser Ile 1 5 10 15 His Val Val Thr Trp Asn Val Ala Ser Ala Ala ProPro Leu Asp Leu 20 25 30 Ser Asp Leu Leu Gln Leu Asn Asn Arg Asn Leu AsnLeu Asp Ile Tyr 35 40 45 Val Ile Gly Leu Gln Glu Leu Asn Ser Gly Ile IleSer Leu Leu Ser 50 55 60 Asp Ala Ala Phe Asn Asp Ser Trp Ser Ser Phe LeuMet Asp Val Leu 65 70 75 80 Ser Pro Leu Ser Phe Ile Lys Val Ser His ValArg Met Gln Gly Ile 85 90 95 Leu Leu Leu Val Phe Ala Lys Tyr Gln His LeuPro Tyr Ile Gln Ile 100 105 110 Leu Ser Thr Lys Ser Thr Pro Thr Gly LeuPhe Gly Tyr Trp Gly Asn 115 120 125 Lys Gly Gly Val Asn Ile Cys Leu LysLeu Tyr Gly Tyr Tyr Val Ser 130 135 140 Ile Ile Asn Cys His Leu Pro ProHis Ile Ser Asn Asn Tyr Gln Arg 145 150 155 160 Leu Glu His Phe Asp ArgIle Leu Glu Met Gln Asn Cys Glu Gly Arg 165 170 175 Asp Ile Pro Asn IleLeu Asp His Asp Leu Ile Ile Trp Phe Gly Asp 180 185 190 Met Asn Phe ArgIle Glu Asp Phe Gly Leu His Phe Val Arg Glu Ser 195 200 205 Ile Lys AsnArg Cys Tyr Gly Gly Leu Trp Glu Lys Asp Gln Leu Ser 210 215 220 Ile AlaLys Lys His Asp Pro Leu Leu Arg Glu Phe Gln Glu Gly Arg 225 230 235 240Leu Leu Phe Pro Pro Thr Tyr Lys Phe Asp Arg Asn Ser Asn Asp Tyr 245 250255 Asp Thr Ser Glu Lys Lys Arg Lys Pro Ala Trp Thr Asp Arg Ile Leu 260265 270 Trp Arg Leu Lys Arg Gln Pro Cys Ala Gly Pro Asp Thr Pro Ile Pro275 280 285 Pro Ala Ser His Phe Ser Leu Ser Leu Arg Gly Tyr Ser Ser HisMet 290 295 300 Thr Tyr Gly Ile Ser Asp His Lys Pro Val Ser Gly Thr PheAsp Leu 305 310 315 320 Glu Leu Lys Pro Leu Val Ser Ala Pro Leu Ile ValLeu Met Pro Glu 325 330 335 Asp Leu Trp Thr Val Glu Asn Asp Met Met ValSer Tyr Ser Ser Thr 340 345 350 Ser Asp Phe Pro Ser Ser Pro Trp Asp TrpIle Gly Leu Tyr Lys Val 355 360 365 Gly Leu Arg Asp Val Asn Asp Tyr ValSer Tyr Ala Trp Val Gly Asp 370 375 380 Ser Lys Val Ser Cys Ser Asp AsnLeu Asn Gln Val Tyr Ile Asp Ile 385 390 395 400 Ser Asn Ile Pro Thr ThrGlu Asp Glu Phe Leu Leu Cys Tyr Tyr Ser 405 410 415 Asn Ser Leu Arg SerVal Val Gly Ile Ser Arg Pro Phe Gln Ile Pro 420 425 430 Pro Gly Ser LeuArg Glu Asp Pro Leu Gly Glu Ala Gln Pro Gln Ile 435 440 445

What is claimed is:
 1. A method of identifying a candidate p53 pathwaymodulating agent, said method comprising the steps of: (a) providing anassay system comprising a purified PIB polypeptide or nucleic acid or afunctionally active fragment or derivative thereof; (b) contacting theassay system with a test agent under conditions whereby, but for thepresence of the test agent, the system provides a reference activity;and (c) detecting a test agent-biased activity of the assay system,wherein a difference between the test agent-biased activity and thereference activity identifies the test agent as a candidate p53 pathwaymodulating agent.
 2. The method of claim 1 wherein the assay systemcomprises cultured cells that express the PIB polypeptide.
 3. The methodof claim 2 wherein the cultured cells additionally have defective p53function.
 4. The method of claim 1 wherein the assay system includes ascreening assay comprising a PIB polypeptide, and the candidate testagent is a small molecule modulator.
 5. The method of claim 4 whereinthe assay is a phosphatase assay.
 6. The method of claim 1 wherein theassay system is selected from the group consisting of an apoptosis assaysystem, a cell proliferation assay system, an angiogenesis assay system,and a hypoxic induction assay system.
 7. The method of claim 1 whereinthe assay system includes a binding assay comprising a PIB polypeptideand the candidate test agent is an antibody.
 8. The method of claim 1wherein the assay system includes an expression assay comprising a PIBnucleic acid and the candidate test agent is a nucleic acid modulator.9. The method of claim 8 wherein the nucleic acid modulator is anantisense oligomer.
 10. The method of claim 8 wherein the nucleic acidmodulator is a PMO.
 11. The method of claim 1 additionally comprising:(d) administering the candidate p53 pathway modulating agent identifiedin (c) to a model system comprising cells defective in p53 function and,detecting a phenotypic change in the model system that indicates thatthe p53 function is restored.
 12. The method of claim 11 wherein themodel system is a mouse model with defective p53 function.
 13. A methodfor modulating a p53 pathway of a cell comprising contacting a celldefective in p53 function with a candidate modulator that specificallybinds to a PIB polypeptide comprising an amino acid sequence selectedfrom group consisting of SEQ ID NOs:10, 11, 12, 13, and 14, whereby p53function is restored.
 14. The method of claim 13 wherein the candidatemodulator is administered to a vertebrate animal predetermined to have adisease or disorder resulting from a defect in p53 function.
 15. Themethod of claim 13 wherein the candidate modulator is selected from thegroup consisting of an antibody and a small molecule.
 16. The method ofclaim 1, comprising the additional steps of: (d) providing a secondaryassay system comprising cultured cells or a non-human animal expressingPIB, (e) contacting the secondary assay system with the test agent of(b) or an agent derived therefrom under conditions whereby, but for thepresence of the test agent or agent derived therefrom, the systemprovides a reference activity; and (f) detecting an agent-biasedactivity of the second assay system, wherein a difference between theagent-biased activity and the reference activity of the second assaysystem confirms the test agent or agent derived therefrom as a candidatep53 pathway modulating agent, and wherein the second assay detects anagent-biased change in the p53 pathway.
 17. The method of claim 16wherein the secondary assay system comprises cultured cells.
 18. Themethod of claim 16 wherein the secondary assay system comprises anon-human animal.
 19. The method of claim 18 wherein the non-humananimal mis-expresses a p53 pathway gene.
 20. A method of modulating p53pathway in a mammalian cell comprising contacting the cell with an agentthat specifically binds a PIB polypeptide or nucleic acid.
 21. Themethod of claim 20 wherein the agent is administered to a mammaliananimal predetermined to have a pathology associated with the p53pathway.
 22. The method of claim 20 wherein the agent is a smallmolecule modulator, a nucleic acid modulator, or an antibody.
 23. Amethod for diagnosing a disease in a patient comprising: (a) obtaining abiological sample from the patient; (b) contacting the sample with aprobe for PIB expression; (c) comparing results from step (b) with acontrol; (d) determining whether step (c) indicates a likelihood ofdisease.
 24. The method of claim 23 wherein said disease is cancer. 25.The method according to claim 24, wherein said cancer is a cancer asshown in Table 1 as having >25% expression level.